Fused pyrimidine compounds and use thereof

ABSTRACT

The present invention provides fused pyrimidine compounds of the general Formula (I): 
                         
or a salt thereof, wherein the variables are as defined in the specification. Fused pyrimidine compounds of the general Formula (I) are provided as kinase inhibitors, such as multi-kinase inhibitors. In one aspect, fused pyrimidine compounds of the general Formula (I) are provided as IGF-IR inhibitors. The compounds may be used in a method of treating cancer. Pharmaceutical compositions containing a fused pyrimidine compounds of the general Formula (I) and a pharmaceutically acceptable carrier are also provided, as are kits containing a fused pyrimidine compound of the general Formula (I) or salt thereof and instructions for use, e.g., in a method of treating cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional PatentApplication No. 61/746,088, filed Dec. 26, 2012 and U.S. ProvisionalPatent Application No. 61/798,842, filed Mar. 15, 2013, the disclosuresof which are incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinasemembrane receptor having a structure very similar to that of the insulinreceptor (IR). The structure of IGF-IR consists of two extracellularα-chains that form the ligand-binding domain and two β-chains that makeup the transmembrane and intracellular domains. IGF-IR is the primaryreceptor for insulin-like growth factor IGF-I, although IGF-II andinsulin can also bind with less affinity. Upon ligand binding, IGF-IR isactivated, resulting in autophosphorylation of tyrosines on theintracellular β-subunit. IGF-IR then phosphorylates intracellularproteins such as the insulin receptor substrates 1 to 4 (IRS1-IRS4) andShc. These substrates, in turn, initiate phosphorylation cascades thatactivate the phosphatidylinositol 3-kinase (PI-3K)/protein kinase B(Akt) or mitogen-activated protein kinase (MAPK) pathways (Samani et al.Endocr. Rev. 28:20-47 (2007)).

Through activation of these signaling cascades, IGF-IR has beenimplicated in cancer. The exact role of IGF-IR in cancer, however,remains uncertain and appears to vary according to tumor or cell type.For example, some tumors may depend on IGF-IR signaling for survival,whereas others rely on IGF-IR for proliferation. Yet other tumors mayemploy IGF-IR overexpression as a mechanism of resistance againstcytotoxic agents such as anti-cancer drugs (Rodon et al. Mol. CancerTher. 7:2575-2588 (2008)). Accordingly, inhibition of IGF-IR is anattractive drug strategy for cancer treatment.

Although IGF-IR was first cloned in the 1980s, drug development totarget IGF-IR has been slow to develop. Currently, there are close to 30drug candidates that target IGF-IR in various clinical phases includingboth monoclonal antibodies and small molecule tyrosine kinaseinhibitors, but no molecule has yet received FDA approval for cancertreatment (Rodon et al. Mol. Cancer Ther. 7:2575-2588 (2008); Gualbertoet al. Oncogene 28:3009-3021 (2009)). There remains a clear need totarget IGF-IR through the development of potent inhibitors of thisreceptor.

BRIEF SUMMARY OF THE INVENTION

Fused pyrimidine compounds of the general Formula (I) are described asnew kinase modulators, such as modulators of anyone or more of thekinases of Tables B7-B13. The fused pyrimidine compounds of the generalFormula (I) in one aspect are multi-kinase modulators. In one aspect,the fused pyrimidine compounds of the general Formula (I) are describedas new insulin-like growth factor-I receptor modulators. Other compoundsare also detailed herein. Compositions and kits comprising a compoundare provided, as are methods of using and making the compounds. Otherfused pyrimidine compounds are also provided. Compounds of the inventionmay also find use in treating of cancer. Compounds of the invention mayalso find use in treating diseases and/or conditions in which modulationof a kinase (e.g., one or more of the kinases of Tables B7-B13) may beimplicated in therapy. Compounds of the invention may also find use intreating diseases and/or conditions in which modulation of insulin-likegrowth factor-I receptors may be implicated in therapy. Compoundsdisclosed herein may find use in the methods disclosed herein, includinguse in treating, preventing, delaying the onset and/or delaying thedevelopment of cancer in an individual in need thereof, such as a human.

In one variation, provided are compounds of the Formula (I):

or a salt thereof, wherein:

D is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, or taken together with R^(D) and the nitrogen to whichthey are attached to form a substituted or unsubstituted heterocyclyl;

E is substituted or unsubstituted heteroaryl;

each j, k, m, and n is independently 0 or 1;

each R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8),R^(A9) and R^(A10) where present, is independently hydrogen, substitutedor unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or taken together with a geminal R^(A(1-10))group and the carbon to which they are attached to form carbonyl,thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl;

R^(D) is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, or takentogether with D and the nitrogen to which they are attached to form asubstituted or unsubstituted heterocyclyl;

X is O or S;

R^(Z) is hydrogen, or substituted or unsubstituted C₁-C₆ alkyl;

each R^(Z1) and R^(Z2) is independently hydrogen, or substituted orunsubstituted C₁-C₆ alkyl, or R^(Z1) and R^(Z2) are taken together withthe carbon to which they are attached to form a carbonyl or a C₃-C₆cycloalkyl;

each R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present,is independently hydrogen, substituted or unsubstituted C₁-C₆ alkyl,halo, hydroxy, —OR¹, —O—C₁-C₆ alkylene-P(O)(OH)₂, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or taken together with a geminal R^(Z(3-8))group and the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl;

each p is independently 0, 1 or 2;

each R¹ is independently a substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted orunsubstituted aryl;

each R² is independently a substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted aryl or hydroxyl;

each R³, R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, substituted orunsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl; and

each R⁸ and R⁹ is independently hydrogen, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In one variation, the compound is of Formula I, or a salt thereof, and jand k are each 0. In another variation, R^(A1), R^(A2), R^(A3), R^(A4),R^(A5) and R^(A6) are each hydrogen. In another variation, R^(A1) andR^(A2) are each C₁-C₆ alkyl and R^(A3), R^(A4), R^(A5) and R^(A6) areeach hydrogen. In another variation, R^(A1) and R^(A2) are each methyl.In another variation, R^(A3) and R^(A4) are each C₁-C₆ alkyl and R^(A1),R^(A2), R^(A5) and R^(A6) are each hydrogen. In another variation,R^(A3) and R^(A4) are each methyl. In another variation, R^(A5) andR^(A6) are each C₁-C₆ alkyl and R^(A1), R^(A2), R^(A3) and R^(A4) areeach hydrogen. In another variation, R^(A5) and R^(A6) are each methyl.In another variation, R^(A3) and R^(A4) are taken together to formsubstituted or unsubstituted cyclopropyl and R^(A1), R^(A2), R^(A5) andR^(A6) are each hydrogen. In another variation, R^(A3) and R^(A4) aretaken together to form substituted or unsubstituted oxiranyl and R^(A1),R^(A2), R^(A5) and R^(A6) are each hydrogen. In another variation,R^(A3) and R^(A4) are taken together to form carbonyl and R^(A1),R^(A2), R^(A5) and R^(A6) are each hydrogen. In another variation,R^(A3) and R^(A4) are taken together to form thiocarbonyl and R^(A1),R^(A2), R^(A5) and R^(A6) are each hydrogen. In another variation,R^(A3) and R^(A4) are each halogen and R^(A1), R^(A2), R^(A5) and R^(A6)are each hydrogen. In another variation, R^(A3) and R^(A4) are eachfluorine.

In another variation, the compound is of Formula I, or a salt thereof,and j is 1 and k is 0. In another variation, R^(A1), R^(A2), R^(A3),R^(A4), R^(A5), R^(A6), R^(A7) and R^(A8) are each hydrogen.

In another variation, j and k are each 1. In another variation, R^(A1),R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) andR^(A10) are each hydrogen.

In another variation, the compound is of Formula I, or a salt thereof,and m and n are each 0. In another variation, each R^(Z1), R^(Z2),R^(Z3) and R^(Z4) is hydrogen.

In another variation, the compound is of Formula I, or a salt thereof,and m is 1 and n is 0. In another variation, each R^(Z1), R^(Z2), R^(Z3)and R^(Z4) is hydrogen. In another variation, R^(Z5) and R^(Z6) are eachhydrogen. In another variation, R^(Z5) is hydroxy and R^(Z6) ishydrogen. In another variation, R^(Z3) is hydroxy and R^(Z4) ishydrogen. In another variation, R^(Z5) is C₁-C₆ alkoxy and R^(Z6) ishydrogen. In another variation, R^(Z5) is methoxy. In another variation,R^(Z5) is halogen and R^(Z6) is hydrogen. In another variation, R^(Z5)is fluorine. In another variation, R^(Z5) and R^(Z6) are eachsubstituted or unsubstituted C₁-C₆ alkyl. In another variation, R^(Z5)and R^(Z6) are each methyl. In another variation, R^(Z5) is substitutedor unsubstituted heteroaryl and R^(Z6) is hydrogen. In anothervariation, R^(Z5) is substituted tetrazolyl. In another variation,R^(Z5) and R^(Z6) are each halogen. In another variation, R^(Z5) andR^(Z6) are each fluorine. In another variation, R^(Z5) is —O—C₁-C₆alkylene-P(O)(OH)₂, and R^(Z6) is hydrogen. In another variation, R^(Z5)is —OC(O)R⁸ and R^(Z6) is hydrogen.

In another variation, the compound is of Formula I, or a salt thereof,and m and n are each 1. In another variation, R^(Z3), R^(Z4), R^(Z5),R^(Z6), R^(Z7) and R^(Z8) are each hydrogen. In another variation, R^(Z)is hydrogen. In another variation, R^(Z) is substituted or unsubstitutedC₁-C₆ alkyl. In another variation, R^(Z) is unsubstituted C₁-C₆ alkyl.In another variation, R^(Z) is methyl.

In another variation, the compound is of Formula I, or a salt thereof,and R^(D) is hydrogen. In another variation, R^(D) is substituted orunsubstituted C₁-C₆ alkyl.

In another variation, the compound is of Formula I, or a salt thereof,and D is hydrogen. In another variation, D is substituted orunsubstituted C₁-C₆ alkyl. In another variation, D is substituted orunsubstituted phenyl, substituted or unsubstituted pyridyl, substitutedor unsubstituted pyrimidyl, substituted or unsubstituted pyrazinyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedthiadiazolyl, substituted or unsubstituted C₃-C₈ cycloalkyl, orsubstituted or unsubstituted heterocyclyl. In another variation, D issubstituted or unsubstituted phenyl. In another variation, D issubstituted or unsubstituted pyridyl. In another variation, D isunsubstituted pyridyl. In another variation, D is substituted pyridyl.In another variation, D is selected from the group consisting of3-pyridyl and 6-fluoro-3-pyridyl. In another variation, D is substitutedor unsubstituted pyrimidyl. In another variation, D is unsubstitutedpyrimidyl. In another variation, D is pyrimid-5-yl. In anothervariation, D is substituted pyrimidyl. In another variation, D issubstituted or unsubstituted pyrazinyl. In another variation, D ispyrazin-2-yl. In another variation, D is substituted pyrazinyl. Inanother variation, D is substituted or unsubstituted thiazolyl. Inanother variation, D is unsubstituted thiazolyl. In another variation, Dis substituted thiazolyl. In another variation, D is5-chlorothiazol-2-yl. In another variation, D is substituted orunsubstituted thiadiazolyl. In another variation, D is unsubstitutedthiadiazolyl. In another variation, D is substituted or unsubstitutedC₃-C₈ cycloalkyl. In another variation, D is substituted orunsubstituted heterocyclyl. In another variation, D is substituted orunsubstituted pyrrolidin-3-yl. In another variation, D is substituted orunsubstituted piperidin-3-yl. In another variation, D is1-(2-amino-2-methylpropanoyl)piperidin-3-yl. In another variation, D is1-isopropylpiperidin-3-yl. In another variation, D is taken togetherwith R^(D) and the nitrogen to which they are attached to form asubstituted or unsubstituted heterocyclyl. In another variation, D istaken together with R^(D) and the nitrogen to which they are attached toform a substituted azetidinyl. In another variation, D is taken togetherwith R^(D) and the nitrogen to which they are attached to form3-aminoazetidinyl.

In another variation, the compound is of Formula I, or a salt thereof,and E is a substituted or unsubstituted 5-membered heteroaryl. Inanother variation, E is a substituted or unsubstituted pyrazolyl. Inanother variation, E is a substituted pyrazolyl. In another variation, Eis selected from the group consisting of 5-cyclopropylpyrazol-3-yl,5-cyclopentylpyrazol-3-yl, 5-(isopropyl)pyrazol-3-yl,3-cyclopropylpyrazol-5-yl, 3-cyclopentylpyrazol-5-yl and3-(isopropyl)pyrazol-5-yl. In another variation, E is a substituted orunsubstituted imidazolyl. In another variation, E is a substituted orunsubstituted isoxazolyl. In another variation, E is a substituted orunsubstituted oxazole. In another variation, E is a substituted orunsubstituted thiazole.

In another variation, the compound of Formula I, or a salt thereof, isselected from the group consisting of:

-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;-   1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N-dimethylpyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (3-aminoazetidin-1-yl)(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)methanone;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(piperidin-3-yl)pyrrolidine-2-carboxamide;-   N-(1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,1′-cyclopropan]-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,2′-oxiran]-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate;-   2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine    1-oxide;-   2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    1-oxide;-   2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    3-oxide;-   N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone;-   (1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole    2-oxide;-   N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;-   N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;-   N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;-   N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;    and-   N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide.

In another variation, the compound of Formula I, or a salt thereof, isselected from the group consisting of:

-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2R,3R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (2S,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (2R,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (2S,3R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;-   (R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N-dimethylpyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N-dimethylpyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-(3-aminoazetidin-1-yl)(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)methanone;-   (S)-(3-aminoazetidin-1-yl)(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)methanone;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N—((R)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N—((S)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N—((S)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N—((R)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4S)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2R,4S)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4R)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (R)—N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)-4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;-   (S)-3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;-   (S)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;-   (S)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,1′-cyclopropan]-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,1′-cyclopropan]-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,2′-oxiran]-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,2′-oxiran]-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2S,4S)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2R,4S)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2S,4R)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate-   (R)-2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine    1-oxide;-   (S)-2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine    1-oxide;-   (R)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    1-oxide;-   (S)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    1-oxide;-   (R)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    3-oxide;-   (S)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    3-oxide;-   (R)—N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((R)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((S)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((S)-5-hydr    oxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((R)-5-hydr    oxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5R,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5R,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5S,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5S,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5R,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5R,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5S,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5S,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (2R,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide-   (R)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone;-   (S)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone;-   (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone;-   (S)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole    2-oxide;-   (S)-3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole    2-oxide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;-   (R,R)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;-   (R)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,R)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R,S)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S,R)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S,S)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;    and-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;    and-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide.

Where aspects or embodiments of the invention are described in terms ofa Markush group or other grouping of alternatives, the present inventionencompasses not only the entire group listed as a whole, but each memberof the group individually and all possible subgroups of the main group,but also the main group absent one or more of the group members. Thepresent invention also envisages the explicit exclusion of one or moreof any of the group members in the claimed invention. For example, insome embodiments, provided is a compound selected from a groupconsisting of any one or more of Compound Nos. 1-96, such as a groupconsisting of any one or any two or any three or more of Compound Nos.1-96, or a salt thereof. A selection of any combination of Compound Nos.1-96, or salts thereof, is intended the same as if each and everycombination were specifically and individually listed. In someembodiments, the compound of Formula I, or a salt thereof, is selectedfrom the group consisting of Compound Nos. 1-96. In some embodiments,the compound of Formula I, or a salt thereof, is selected from the groupconsisting of Compound Nos. 1-67.

In another variation, the compound of Formula I is a compound of theformula (I-A):

or a salt thereof, where R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6),R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6), D and E are asdefined for Formula (I). In one variation, each of R^(A1), R^(A2),R^(A3), R^(A4), R^(A5) and R^(A6) is independently hydrogen, substitutedor unsubstituted C₁-C₆ alkyl, halo, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted heterocyclyl, or is takentogether with a geminal R^(A(1-6)) group and the carbon to which theyare attached to form a carbonyl or a thiocarbonyl group. In anothervariation, each of R^(Z1), R^(Z2), R^(Z3) and R^(Z4) is hydrogen. Inanother variation, each of R^(Z5) and R^(Z6) is hydrogen. In anothervariation, R^(Z5) is hydroxyl or —OR¹ and R^(Z6) is hydrogen. In anothervariation, R^(Z3) is hydroxyl and R^(Z4) is hydrogen. In anothervariation, R^(Z5) is C₁-C₆ alkoxy and R^(Z6) is hydrogen. In anothervariation, R^(Z5) is methoxy. In another variation, R^(Z5) is halogenand R^(Z6) is hydrogen. In another variation, R^(Z5) is fluoro. Inanother variation, each of R^(Z5) and R^(Z6) is substituted orunsubstituted C₁-C₆ alkyl. In another variation, each of R^(Z5) andR^(Z6) is methyl. In another variation, R^(Z5) is substituted orunsubstituted heteroaryl and R^(Z6) is hydrogen. In another variation,R^(Z5) is substituted tetrazolyl. In another variation, each of R^(Z5)and R^(Z6) is halogen. In another variation, each of R^(Z5) and R^(Z6)is fluoro. In another variation, R^(Z5) is —O—C₁-C₆ alkylene-P(O)(OH)₂,and R^(Z6) is hydrogen. In another variation, R^(Z5) is —OC(O)R⁸ andR^(Z6) is hydrogen. In another variation, R^(Z) is hydrogen or methyl.In another variation, D is substituted or unsubstituted pyridyl,substituted or unsubstituted pyrimidyl, or substituted or unsubstitutedpyrazinyl. In another variation, D is selected from the group consistingof 6-fluoro-3-pyridyl, 3-pyridyl, pyrimid-5-yl and pyrazin-2-yl. Inanother variation, D is substituted or unsubstituted C₁-C₆ alkyl. Inanother variation, D is methyl. In another variation, D is substitutedor unsubstituted piperidin-3-yl. In another variation, D is1-(2-amino-2-methylpropanoyl)piperidin-3-yl. In another variation, D is1-isopropylpiperidin-3-yl. In another variation, D is substituted orunsubstituted thiazolyl. In another variation, D is substituted orunsubstituted thiadiazolyl. In another variation, D is substituted orunsubstituted pyrrolidin-3-yl. In another variation, E is substituted orunsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl,substituted or unsubstituted imidazolyl, substituted or unsubstitutedoxazole, or substituted or unsubstituted thiazole. In another variation,E is selected from the group consisting of 5-cyclopropylpyrazol-3-yl,5-cyclopentylpyrazol-3-yl, 5-(isopropyl)pyrazol-3-yl,3-cyclopropylpyrazol-5-yl, 3-cyclopentylpyrazol-5-yl,3-(isopropyl)pyrazol-5-yl, and 3-(isopropyl)isoxazol-5-yl.

Further provided is a pharmaceutical composition comprising a compoundof Formula I or any variations described herein, or a salt thereof, anda pharmaceutically acceptable carrier.

Further provided is a method of treating cancer comprising administeringto an individual in need thereof a therapeutically effective amount of acompound of Formula I or any variations described herein, or apharmaceutically acceptable salt thereof.

Further provided is use of a compound of Formula I or any variationsdescribed herein, or a salt thereof, in the manufacturing of amedicament for the treatment of cancer.

Also provided is a kit comprising a compound of Formula I or anyvariations described herein, or a pharmaceutically acceptable saltthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shown reduction in tumor burden in a COLO205 xenograft model ofhuman colon cancer using Compound 8b. The term “compound’ in someinstances are abbreviated as “cpd” or “cmpd”.

FIG. 2 shows reduction in tumor burden in an MCF7 xenograft model ofhuman breast cancer using Compound 8b.

FIG. 3 shows the effect of Compound 8b on body weight in a COLO205xenograft model of human colon cancer.

FIG. 4 shows the effect of Compound 8b on body weight in an MCF7xenograft model of human breast cancer.

DETAILED DESCRIPTION OF THE INVENTION

Definition

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

“Alkyl” as used herein refers to and includes, unless otherwise stated,linear (i.e. unbranched) or branched univalent hydrocarbon structuresand combinations thereof, which may be fully saturated, mono- orpolyunsaturated, having the number of carbon atoms designated (i.e.,C₁-C₁₀ means one to ten carbon atoms). Particular alkyl groups are thosehaving 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”), having 1 to 8 carbonatoms (a “C₁-C₈ alkyl”), having 1 to 6 carbon atoms (a “C₁-C₆ alkyl”),having 2 to 6 carbon atoms (a “C₂-C₆ alkyl”), or having 1 to 4 carbonatoms (a “C₁-C₄ alkyl”). Examples of saturated alkyl group include, butare not limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. “Alkenyl” refers to an unsaturated hydrocarbon group having atleast one site of olefinic unsaturation (i.e., having at least onemoiety of the formula C═C) and preferably having from 2 to 10 carbonatoms (a “C₂-C₁₀ alkenyl”) and more preferably 2 to 6 carbon atoms (a“C₂-C₆ alkenyl”) and the like. “Alkynyl” refers to an unsaturatedhydrocarbon group having at least one site of acetylenic unsaturation(i.e., having at least one moiety of the formula C≡C) and preferablyhaving from 2 to 10 carbon atoms (a “C₂-C₁₀ alkynyl”) and morepreferably 2 to 6 carbon atoms (a “C₂-C₆ alkynyl”) and the like.

“Substituted alkyl”, “substituted alkenyl” and “substituted alkynyl”refer to an alkyl, alkenyl or alkynyl group, respectively, having from 1to 5 substituents including, but not limited to, substituents such asalkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy,aryloxy, substituted aryloxy, acyl, acyloxy, carbonylalkoxy, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,substituted or unsubstituted heterocyclyl, amino, substituted amino,cyano, halo, hydroxy, nitro, carboxy, thiol, thioalkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Alkylene” as used herein refers to the same residues as alkyl, buthaving bivalency. Examples of alkylene include methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—),and the like.

“Cycloalkyl” as used herein refers to and includes cyclic univalenthydrocarbon structures, which may be fully saturated, mono- orpolyunsaturated, having the number of carbon atoms designated (i.e.,C₁-C₁₀ means one to ten carbon atoms). Cycloalkyl can consist of onering, such as cyclohexyl, or multiple rings, such as adamantly, butexcludes aryl groups. A cycloalkyl comprising more than one ring may befused, spiro or bridged, or combinations thereof. A preferred cycloalkylis a cyclic hydrocarbon having from 3 to 12 annular carbon atoms. A morepreferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annularcarbon atoms (a “C₃-C₈ cycloalkyl”), or having 3 to 6 carbon atoms (a“C₃-C₆ cycloalkyl”). Examples of cycloalkyl include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, norbornyl, and the like. “Cycloalkenyl”refers to an unsaturated cycloalkyl group having at least one site ofolefinic unsaturation (i.e., having at least one moiety of the formulaC═C), which can consist of one ring, such as cyclohexyl, or multiplerings, such as norbornenyl. A preferred cycloalkenyl is an unsaturatedcyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkenyl”). Examples of cycloalkenyl groups include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Aryl” or “Ar” as used herein refers to an unsaturated aromaticcarbocyclic group having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic. In one variation, the aryl group contains from 6 to14 annular carbon atoms (a “C₆-C₁₄ aryl”). An aryl group having morethan one ring where at least one ring is non-aromatic may be connectedto the parent structure at either an aromatic ring position or at anon-aromatic ring position. In one variation, an aryl group having morethan one ring where at least one ring is non-aromatic is connected tothe parent structure at an aromatic ring position.

“Heteroaryl” or “HetAr” as used herein refers to an unsaturated aromaticcarbocyclic group having from 1 to 10 annular carbon atoms and at leastone annular heteroatom, including but not limited to heteroatoms such asnitrogen, oxygen and sulfur. A heteroaryl group may have a single ring(e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein refersto a saturated or an unsaturated non-aromatic group having a single ringor multiple condensed rings, and having from 1 to 10 annular carbonatoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur oroxygen, and the like. A heterocycle comprising more than one ring may befused, spiro or bridged, or any combination thereof. In fused ringsystems, one or more of the rings can be aryl or heteroaryl. Aheterocycle having more than one ring where at least one ring isaromatic is connected to the parent structure at a non-aromatic ringposition.

“Substituted cycloalkyl”, “substituted aryl”, “substituted heteroaryl”,and “substituted heterocyclyl” as used herein respectively refer to acycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclylgroup having 1 to 5 substituents including, but not limited to, groupssuch as alkoxy, substituted alkoxy, cycloalkoxy, substitutedcycloalkoxy, aryloxy, substituted aryloxy, acyl, acyloxy,carbonylalkoxy, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, amino, substituted amino, cyano, halo, hydroxy, nitro,carboxy, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like.

“Alkoxy” as used herein refers to the group “alkyl-O—”, which includes,by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, andthe like. Similarly, “cycloalkoxy” refers to the group “cycloalkyl-O—”and “aryloxy” refers to the group “aryl-O—”. “Substituted alkoxy” refersto the group “substituted alkyl-O—”. “Substituted cycloalkoxy” refers tothe group “substituted cycloalkyl-O—”. “Substituted aryloxy” refers tothe group “substituted aryl-O—”.

“Acyl” as used herein refers to the groups —C(O)-alkyl,—C(O)-substituted alkyl, —C(O)-cycloalkyl, —C(O)-substituted cycloalkyl,—C(O)-aryl, C(O)-substituted aryl, —C(O)-heteroaryl, —C(O)-substitutedheteroaryl, —C(O)-heterocyclyl or —C(O)-substituted heterocyclyl.

“Acyloxy” as used herein refers to the groups —OC(O)-alkyl,—OC(O)-substituted alkyl, —OC(O)-cycloalkyl, —OC(O)-substitutedcycloalkyl, —OC(O)-aryl, —OC(O)-substituted aryl, —OC(O)-heteroaryl,—OC(O)-substituted heteroaryl, —OC(O)-heterocyclyl or —OC(O)-substitutedheterocyclyl.

“Carbonylalkoxy” as used herein refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, 13 C(O)O-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-heteroaryl,—C(O)O-substituted heteroaryl, —C(O)O-heterocyclyl or —C(O)O-substitutedheterocyclyl.

“Substituted amino” as used herein refers to the group —NR_(a)R_(b),where (a) each R_(a) and R_(b) group is independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, substituted heterocyclyl, provided that bothR_(a) and R_(b) groups are not hydrogen, or (b) R_(a) and R_(b) aretaken together with the nitrogen atom to which they are attached to forma heterocyclic ring. “Unsubstituted amino” as used herein refers to thegroup NH₂.

“Acylamino” as used herein refers to the group —C(O)NR_(a)R_(b) whereR_(a) and R_(b) are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, substituted heterocyclyl, or R_(a) and R_(b) are takentogether with the nitrogen atom to which they are attached to form aheterocyclic ring.

“Aminoacyl” as used herein refers to the group —NR_(a)C(O)R_(b) whereeach R_(a) and R_(b) group is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, substituted heterocyclyl. Preferably, R_(a) ishydrogen or alkyl.

“Sulfonyl” as used herein refers to the groups —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclyl or —SO₂-substituted heterocyclyl.

“Sulfonylamino” as used herein refers to the group —SO₂N(R_(a))R_(b)where each R_(a) and R_(b) group is independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclyl, substituted heterocyclyl.

“Aminosulfonyl” as used herein refers to the group —NR_(a)SO₂R_(b) wherethe R_(a) group is selected from the group consisting of hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl,substituted heterocyclyl, and the R_(b) group is selected from the groupconsisting of alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclyl, substituted heterocyclyl.

“Aminocarbonylalkoxy” as used herein refers to the group—NR_(a)C(O)OR_(b) where each R_(a) and R_(b) group is independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclyl, substitutedheterocyclyl.

“Carbonylalkylenealkoxy” as used herein refers to the group—C(═O)—(CH₂)_(n)—OR where R is a substituted or unsubstituted alkyl andn is an integer from 1 to 100, more preferably n is an integer from 1 to10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each hydrogenis replaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Thiocarbonyl” refers to the group C═S.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thiol” as used herein when referring to a substituent refers to thegroups —SH.

“Thioalkyl” refers to the groups —S-alkyl.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a primate, human, bovine,horse, feline, canine, or rodent.

As used herein a receptor “modulator,” such as an IGF-IR modulator,encompasses both a receptor antagonist and a receptor agonist (e.g., an“IGF-IR modulator” encompasses both an IGF-IR receptor antagonist and anIGF-IR receptor agonist). In some aspects, the receptor modulator bindsto or inhibits binding of a ligand to the receptor and/or reduces oreliminates or increases or enhances or mimics an activity of thereceptor in a reversible or irreversible manner. In some aspects, thereceptor modulator inhibits binding of a ligand to the receptor by atleast about or by about any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95% or 100% as determined by an assay described herein. Insome aspects, the receptor modulator reduces an activity of the receptorby at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95% or 100% as compared to the corresponding activity in thesame subject prior to treatment with the receptor modulator or comparedto the corresponding activity in other subjects not receiving thereceptor modulator. In some aspects, a receptor modulator enhances anactivity of the receptor by at least about or by about any of 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or500% or more as compared to the corresponding activity in the samesubject prior to treatment with the receptor modulator or compared tothe corresponding activity in other subjects not receiving the receptormodulator. In some aspects, the receptor modulator is capable of bindingto the active site of the receptor (e.g., a binding site for a ligand).In some embodiments, the receptor modulator is capable of binding to anallosteric site of the receptor.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For purposesof this invention, beneficial or desired clinical results include, butare not limited to, one or more of the following: decreasing one moresymptoms resulting from the disease, diminishing the extent of thedisease, stabilizing the disease (e.g., preventing or delaying theworsening of the disease), preventing or delaying the spread (e.g.,metastasis) of the disease, preventing or delaying the occurrence orrecurrence of the disease, delay or slowing the progression of thedisease, ameliorating the disease state, providing a remission (whetherpartial or total) of the disease, decreasing the dose of one or moreother medications required to treat the disease, enhancing effect ofanother medication, delaying the progression of the disease, increasingthe quality of life, and/or prolonging survival. Also encompassed by“treatment” is a reduction of pathological consequence of cancer. Themethods of the invention contemplate any one or more of these aspects oftreatment.

As used herein, “delaying” the development of cancer means to defer,hinder, slow, retard, stabilize, and/or postpone development of thedisease. This delay can be of varying lengths of time, depending on thehistory of the disease and/or individual being treated. As is evident toone skilled in the art, a sufficient or significant delay can, ineffect, encompass prevention, in that the individual does not developthe disease. A method that “delays” development of cancer is a methodthat reduces probability of disease development in a given time frameand/or reduces the extent of the disease in a given time frame, whencompared to not using the method. Such comparisons are typically basedon clinical studies, using a statistically significant number ofsubjects. Cancer development can be detectable using standard methods,such as routine physical exams, mammography, imaging, or biopsy.Development may also refer to disease progression that may be initiallyundetectable and includes occurrence, recurrence, and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing cancer. An individual “at risk” may or may not havedetectable disease, and may or may not have displayed detectable diseaseprior to the treatment methods described herein. “At risk” denotes thatan individual has one or more so-called risk factors, which aremeasurable parameters that correlate with development of cancer, whichare described herein. An individual having one or more of these riskfactors has a higher probability of developing cancer than an individualwithout these risk factor(s).

As used herein, by “combination therapy” is meant a therapy thatincludes two or more different compounds. Thus, in one aspect, acombination therapy comprising a compound detailed herein and anothercompound is provided. In some variations, the combination therapyoptionally includes one or more pharmaceutically acceptable carriers orexcipients, non-pharmaceutically active compounds, and/or inertsubstances.

As used herein, the term “effective amount” intends such amount of acompound of the invention which in combination with its parameters ofefficacy and toxicity, should be effective in a given therapeutic form.As is understood in the art, an effective amount may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and asingle agent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any of theco-administered compounds may optionally be lowered due to the combinedaction (e.g., additive or synergistic effects) of the compounds. Invarious embodiments, an effective amount of the composition or therapymay (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii)inhibit, retard, slow to some extent, and preferably stop cancer cellinfiltration into peripheral organs; (iv) inhibit (e.g., slow to someextent and preferably stop) tumor metastasis; (v) inhibit tumor growth;(vi) prevent or delay occurrence and/or recurrence of a tumor; and/or(vii) relieve to some extent one or more of the symptoms associated withthe cancer. In various embodiments, the amount is sufficient toameliorate, palliate, lessen, and/or delay one or more of symptoms ofcancer.

As is understood in the art, an “effective amount” may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and acompound, or pharmaceutically acceptable salt thereof, may be consideredto be given in an effective amount if, in conjunction with one or moreother agents, a desirable or beneficial result may be or is achieved.

A “therapeutically effective amount” refers to an amount of a compoundor salt thereof sufficient to produce a desired therapeutic outcome(e.g., reducing the severity or duration of, stabilizing the severityof, or eliminating one or more symptoms of cancer). For therapeutic use,beneficial or desired results include, e.g., decreasing one or moresymptoms resulting from the disease (biochemical, histologic and/orbehavioral), including its complications and intermediate pathologicalphenotypes presenting during development of the disease, increasing thequality of life of those suffering from the disease, decreasing the doseof other medications required to treat the disease, enhancing effect ofanother medication, delaying the progression of the disease, and/orprolonging survival of patients.

A “prophylactically effective amount” refers to an amount of a compound,or pharmaceutically acceptable salt thereof, sufficient to prevent orreduce the severity of one or more future symptoms of cancer whenadministered to an individual who is susceptible and/or who may developcancer. For prophylactic use, beneficial or desired results include,e.g., results such as eliminating or reducing the risk, lessening theseverity of future disease, or delaying the onset of the disease (e.g.,delaying biochemical, histologic and/or behavioral symptoms of thedisease, its complications, and intermediate pathological phenotypespresenting during future development of the disease).

It is understood that an effective amount of a compound orpharmaceutically acceptable salt thereof, including a prophylacticallyeffective amount, may be given to an individual in the adjuvant setting,which refers to a clinical setting in which an individual has had ahistory of cancer, and generally (but not necessarily) has beenresponsive to therapy, which includes, but is not limited to, surgery(e.g., surgical resection), radiotherapy, and chemotherapy. However,because of their history of the cancer, these individuals are consideredat risk of developing cancer. Treatment or administration in the“adjuvant setting” refers to a subsequent mode of treatment.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, i.e., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Pharmaceutically acceptable salts can be prepared in situ inthe manufacturing process, or by separately reacting a purified compoundof the invention in its free acid or base form with a suitable organicor inorganic base or acid, respectively, and isolating the salt thusformed during subsequent purification.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and the appended claims. Theinvention includes the use of all of the compounds described herein,including any and all stereoisomers, including geometric isomers(cis/trans), salts (including pharmaceutically acceptable salts) andsolvates of the compounds described herein, as well as methods of makingsuch compounds.

In one aspect, provided is a compound of the formula (I):

or a salt thereof, wherein:

D is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, or is taken together with R^(D) and the nitrogen to whichthey are attached to form a substituted or unsubstituted heterocyclyl;

E is substituted or unsubstituted heteroaryl;

each j, k, m, and n is independently 0 or 1;

each R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8),R^(A9) and R^(A10) where present, is independently hydrogen, substitutedor unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminalR^(A(1-10)) group and the carbon to which they are attached to formcarbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl;

R^(D) is hydrogen, substituted or unsubstituted C₁-C₆ alkyl, or takentogether with D and the nitrogen to which they are attached to form asubstituted or unsubstituted heterocyclyl;

X is O or S;

R^(Z) is hydrogen, or substituted or unsubstituted C₁-C₆ alkyl;

each R^(Z1) and R^(Z2) is independently hydrogen, or substituted orunsubstituted C₁-C₆ alkyl, or R^(Z1) and R^(Z2) are taken together withthe carbon to which they are attached to form a carbonyl or a C₃-C₆cycloalkyl;

each R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present,is independently hydrogen, substituted or unsubstituted C₁-C₆ alkyl,halo, hydroxy, —OR¹, —O—C₁-C₆ alkylene-P(O)(OH)₂, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(Z(3-8))group and the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl;

each p is independently 0, 1 or 2;

each R¹ is independently a substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted orunsubstituted aryl;

each R² is independently a substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted aryl or hydroxyl;

each R³, R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, substituted orunsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl; and

each R⁸ and R⁹ is independently hydrogen, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In some embodiments, the compound is of the formula (I), or a saltthereof, and j and k are each 0. In other embodiments, the compound isof the formula (I), or a salt thereof, and j is 1 and k is 0. In otherembodiments, the compound is of the formula (I), or a salt thereof, andj and k are each 1.

In some of these embodiments, each R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10), where present, ishydrogen. In some of these embodiments, at least one of R^(A1), R^(A2),R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10),where present, is substituted or unsubstituted C₁-C₆ alkyl, halo,hydroxy, —OR¹, —SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸,—C(O)R⁹, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or is taken together with ageminal R^(A(1-10)) group and the carbon to which they are attached toform carbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl. Insome of these embodiments, one of R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10), where present, issubstituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH,—S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and the others are hydrogen. Insome of these embodiments, two of R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10), where present, areindependently substituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy,—OR¹, —SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and the others are eachhydrogen. In some of these embodiments, two geminal R^(A(1-10)) groupsof R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8),R^(A9) and R^(A10), where present, are taken together with the carbon towhich they are attached to form carbonyl, thiocarbonyl, a C₃-C₆cycloalkyl, or a heterocyclyl; and the others are each hydrogen. In somevariations, R^(A1) and R^(A2) are each C₁-C₆ alkyl (e.g., methyl), halo(e.g. fluoro), or are taken together with the carbon to which they areattached to form carbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl (e.g.,cyclopropyl), or a heterocyclyl (e.g., oxirane). In some variations,R^(A3) and R^(A4) are each C₁-C₆ alkyl (e.g., methyl), halo (e.g.fluoro), or are taken together with the carbon to which they areattached to form carbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl (e.g.,cyclopropyl), or a heterocyclyl (e.g., oxirane). In some variations,R^(A5) and R^(A6) are each C₁-C₆ alkyl (e.g., methyl), halo (e.g.fluoro), or are taken together with the carbon to which they areattached to form carbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl (e.g.,cyclopropyl), or a heterocyclyl (e.g., oxirane).

In some embodiments, the compound is of the formula (I), or a saltthereof, where j and k are each 0:

In some of these embodiments, each R^(A1), R^(A2), R^(A3), R^(A4),R^(A5) and R^(A6) is hydrogen. In some of these embodiments, at leastone of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) is substitutedor unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(A(1-6))group and the carbon to which they are attached to form carbonyl,thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl. In some of theseembodiments, one of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) issubstituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH,—S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and the others are hydrogen. Insome of these embodiments, two of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5)and R^(A6) are independently substituted or unsubstituted C₁-C₆ alkyl,halo, hydroxy, —OR¹, —SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷,—OC(O)R⁸, —C(O)R⁹, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; and the others areeach hydrogen. In some of these embodiments, two geminal R^(A(1-6))groups of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) are takentogether with the carbon to which they are attached to form carbonyl,thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl; and the others areeach hydrogen. In some variations, R^(A1) and R^(A2) are each C₁-C₆alkyl (e.g., methyl), halo (e.g. fluoro), or are taken together with thecarbon to which they are attached to form carbonyl, thiocarbonyl, aC₃-C₆ cycloalkyl (e.g., cyclopropyl), or a heterocyclyl (e.g., oxirane).In some variations, R^(A3) and R^(A4) are each C₁-C₆ alkyl (e.g.,methyl), halo (e.g. fluoro), or are taken together with the carbon towhich they are attached to form carbonyl, thiocarbonyl, a C₃-C₆cycloalkyl (e.g., cyclopropyl), or a heterocyclyl (e.g., oxirane). Insome variations, R^(A5) and R^(A6) are each C₁-C₆ alkyl (e.g., methyl),halo (e.g. fluoro), or are taken together with the carbon to which theyare attached to form carbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl (e.g.,cyclopropyl), or a heterocyclyl (e.g., oxirane).

In some embodiments, the compound is of the formula (I), or a saltthereof, where j is 1 and k is 0:

In some of these embodiments, each R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7) and R^(A8) is hydrogen. In some of theseembodiments, at least one of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5),R^(A6), R^(A7) and R^(A8) is substituted or unsubstituted C₁-C₆ alkyl,halo, hydroxy, —OR¹, —SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷,—OC(O)R⁸, —C(O)R⁹, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or is taken together witha geminal R^(A(1-8)) group and the carbon to which they are attached toform carbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl. Insome of these embodiments, one of R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7) and R^(A8) is substituted or unsubstituted C₁-C₆alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶,—C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; and theothers are hydrogen. In some of these embodiments, two of R^(A1),R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7) and R^(A8) areindependently substituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy,—OR¹, —SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and the others are eachhydrogen. In some of these embodiments, two geminal R^(A(1-8)) groups ofR^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7) and R^(A8) aretaken together with the carbon to which they are attached to formcarbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl; and theothers are each hydrogen.

In some embodiments, the compound is of the formula (I), or a saltthereof, where j and k are each 1:

In some of these embodiments, each R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10) is hydrogen. In someof these embodiments, at least one of R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10) is substituted orunsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminalR^(A(1-10)) group and the carbon to which they are attached to formcarbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl. In someof these embodiments, one of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5),R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10) is substituted orunsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; and the others are hydrogen. In some of theseembodiments, two of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6),R^(A7), R^(A8), R^(A9) and R^(A10) are independently substituted orunsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; and the others are each hydrogen. In some ofthese embodiments, two geminal R^(A(1-10)) groups of R^(A1), R^(A2),R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10) aretaken together with the carbon to which they are attached to formcarbonyl, thiocarbonyl, a C₃-C₆ cycloalkyl, or a heterocyclyl; and theothers are each hydrogen.

It is intended and understood that each and every variation of j, k,R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8), R^(A9)and R^(A10), where present, described for the formula (I) may becombined with each and every variation of j, k, R^(A1), R^(A2), R^(A3),R^(A4), R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10), wherepresent, and/or each and every variation of m, n, R^(Z), R^(Z1), R^(Z2),R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present, and/oreach and every variation of X, R^(D), D and E described for the formula(I) as if each and every combination is individually described.

In some embodiments, the compound is of the formula (I), or a saltthereof, and m and n are each 1. In some embodiments, the compound is ofthe formula (I), or a salt thereof, and m is 1 and n is 0. In someembodiments, the compound is of the formula (I), or a salt thereof, andm and n are each 0.

In some of these embodiments, R^(Z) is hydrogen. In some of theseembodiments, R^(Z) is substituted or unsubstituted C₁-C₆ alkyl. In onevariation, R^(Z) is unsubstituted C₁-C₆ alkyl (e.g., methyl). In some ofthese embodiments, each R^(Z1) and R^(Z2) is hydrogen. In one variation,each R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present,is hydrogen. In some of these embodiments, R^(Z1) and R^(Z2) areindependently hydrogen, substituted or unsubstituted C₁-C₆ alkyl, ortaken together with the carbon to which they are attached to form acarbonyl or a C₃-C₆ cycloalkyl. In some of these embodiments, one ofR^(Z1) and R^(Z2) is substituted or unsubstituted C₁-C₆ alkyl, or takentogether with the carbon to which they are attached to form a carbonylor a C₃-C₆ cycloalkyl. In some of these embodiments, each R^(Z3),R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present, is hydrogen.In some of these embodiments, at least one of R^(Z3), R^(Z4), R^(Z5),R^(Z6), R^(Z7) and R^(Z8), where present, is substituted orunsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(Z(3-8))group and the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl. In some of these embodiments, one ofR^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present, issubstituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH,—S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and the others are hydrogen. Insome of these embodiments, two geminal R^(Z(3-8)) groups of R^(Z3),R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present, are takentogether with the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl; and the others are each hydrogen. Insome of these embodiments, at least one of R^(Z3), R^(Z4), R^(Z5),R^(Z6), R^(Z7) and R^(Z8), where present, is substituted orunsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. In some of these embodiments, one of R^(Z3),R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present, is halo (e.g.,fluoro), hydroxy, —OR¹ (e.g., OCH₃), or substituted or unsubstitutedheteroaryl (e.g., 5-methyl-2H-tetrazol-2-yl); and the others arehydrogen. In some of these embodiments, R^(Z3) and R^(Z4) are each C₁-C₆alkyl (e.g., methyl) or halo (e.g., fluoro), or taken together with thecarbon to which they are attached to form carbonyl, thiocarbonyl or aC₃-C₆ cycloalkyl. In some of these embodiments, R^(Z5) and R^(Z6) areeach C₁-C₆ alkyl (e.g., methyl) or halo (e.g., fluoro), or takentogether with the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl. In some of these embodiments, one ofR^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8), where present, is aprodrug moiety of the formula —O—C₁-C₆ alkylene-P(O)(OH)₂ (e.g.,—OCH₂P(O)(OH)₂), or —OC(O)R⁸ where R⁸ is C₁-C₆ alkyl (e.g., isopropyl).

In some embodiments, the compound is of the formula (I), or a saltthereof, where m and n are each 0:

In some of these embodiments, each R^(Z1) and R^(Z2) is hydrogen. In onevariation, R^(Z1), R^(Z2), R^(Z3) and R^(Z4) are each hydrogen. In someof these embodiments, R^(Z1) and R^(Z2) are independently hydrogen,substituted or unsubstituted C₁-C₆ alkyl, or taken together with thecarbon to which they are attached to form a carbonyl or a C₃-C₆cycloalkyl. In some of these embodiments, one of R^(Z1) and R^(Z2) issubstituted or unsubstituted C₁-C₆ alkyl, or taken together with thecarbon to which they are attached to form a carbonyl or a C₃-C₆cycloalkyl. In some of these embodiments, each R^(Z3) and R^(Z4) ishydrogen. In some of these embodiments, one of R^(Z3) and R^(Z4) issubstituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH,—S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and the other is hydrogen. Insome of these embodiments, R^(Z3) and R^(Z4) are taken together with thecarbon to which they are attached to form carbonyl, thiocarbonyl or aC₃-C₆ cycloalkyl. In some of these embodiments, at least one of R^(Z3)and R^(Z4) is substituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy,—OR¹, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl.

In some embodiments, the compound is of the formula (I), or a saltthereof, where m is 1 and n is 0:

In some of these embodiments, each R^(Z1) and R^(Z2) is hydrogen. In onevariation, R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5) and R^(Z6) are eachhydrogen. In some of these embodiments, R^(Z1) and R^(Z2) areindependently hydrogen, substituted or unsubstituted C₁-C₆ alkyl, ortaken together with the carbon to which they are attached to form acarbonyl or a C₃-C₆ cycloalkyl. In some of these embodiments, one ofR^(Z1) and R^(Z2) is substituted or unsubstituted C₁-C₆ alkyl, or takentogether with the carbon to which they are attached to form a carbonylor a C₃-C₆ cycloalkyl. In some of these embodiments, each R^(Z3),R^(Z4), R^(Z5) and R^(Z6) is hydrogen. In some of these embodiments, atleast one of R^(Z3), R^(Z4), R^(Z5) and R^(Z6) is substituted orunsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R²,—NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(Z(3-6))group and the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl. In some of these embodiments, one ofR^(Z3), R^(Z4), R^(Z5) and R^(Z6) is substituted or unsubstituted C₁-C₆alkyl, halo, hydroxy, —OR¹, —SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶,—C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; and theothers are hydrogen. In some of these embodiments, two geminalR^(Z(3-6)) groups of R^(Z3), R^(Z4), R^(Z5) and R^(Z6) are takentogether with the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl; and the others are each hydrogen. Insome of these embodiments, at least one of R^(Z3), R^(Z4), R^(Z5) andR^(Z6) is substituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl. In some of these embodiments,one of R^(Z3), R^(Z4), R^(Z5) and R^(Z6) is halo (e.g., fluoro),hydroxy, —OR¹ (e.g., OCH₃), or substituted or unsubstituted heteroaryl(e.g., 5-methyl-2H-tetrazol-2-yl); and the others are hydrogen. In someof these embodiments, R^(Z3) and R^(Z4) are each C₁-C₆ alkyl (e.g.,methyl) or halo (e.g., fluoro), or taken together with the carbon towhich they are attached to form carbonyl, thiocarbonyl or a C₃-C₆cycloalkyl. In some of these embodiments, R^(Z5) and R^(Z6) are eachC₁-C₆ alkyl (e.g., methyl) or halo (e.g., fluoro), or taken togetherwith the carbon to which they are attached to form carbonyl,thiocarbonyl or a C₃-C₆ cycloalkyl. In some of these embodiments, one ofR^(Z3), R^(Z4), R^(Z5) and R^(Z6) is a prodrug moiety of the formula—O—C₁-C₆ alkylene-P(O)(OH)₂ (e.g., —OCH₂P(O)(OH)₂), or —OC(O)R⁸ where R⁸is C₁-C₆ alkyl (e.g., isopropyl).

In some embodiments, the compound is of the formula (I), or a saltthereof, where m and n are each 1:

In some of these embodiments, each R^(Z1) and R^(Z2) is hydrogen. In onevariation, each R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8) ishydrogen. In some of these embodiments, R^(Z1) and R^(Z2) areindependently hydrogen, substituted or unsubstituted C₁-C₆ alkyl, ortaken together with the carbon to which they are attached to form acarbonyl or a C₃-C₆ cycloalkyl. In some of these embodiments, one ofR^(Z1) and R^(Z2) is substituted or unsubstituted C₁-C₆ alkyl, or takentogether with the carbon to which they are attached to form a carbonylor a C₃-C₆ cycloalkyl. In some of these embodiments, each R^(Z3),R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8) is hydrogen. In some of theseembodiments, at least one of R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) andR^(Z8) is substituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹,—SH, —S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or is taken together with ageminal R^(Z(3-8)) group and the carbon to which they are attached toform carbonyl, thiocarbonyl or a C₃-C₆ cycloalkyl. In some of theseembodiments, one of R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8) issubstituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —SH,—S(O)_(p)R², —NR³R⁴, —C(O)NR⁵R⁶, —C(O)OR⁷, —OC(O)R⁸, —C(O)R⁹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and the others are hydrogen. Insome of these embodiments, two geminal R^(Z(3-8)) groups of R^(Z3),R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8) are taken together with thecarbon to which they are attached to form carbonyl, thiocarbonyl or aC₃-C₆ cycloalkyl; and the others are each hydrogen. In some of theseembodiments, at least one of R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) andR^(Z8) is substituted or unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl.

In some embodiments, each R^(A1), R^(A2), R^(A3), R^(A4), R^(A5),R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10), where present, isindependently hydrogen, methyl, fluoro, hydroxyl, or taken together witha geminal R^(A(1-10)) group and the carbon to which they are attached toform a moiety of the structure:

In some embodiments, each R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) andR^(Z8), where present, is independently

In some embodiments, at least one of R^(Z3), R^(Z4), R^(Z5), R^(Z6),R^(Z7) and R^(Z8) is taken together with a geminal R^(Z(3-8)) group andthe carbon to which they are attached to form a carbonyl moiety. In someembodiments, R^(Z3) and R^(Z4) are taken together with the carbon towhich they are attached to form a carbonyl moiety. In some embodiments,R^(Z5) and R^(Z6), where present, are taken together with the carbon towhich they are attached to form a carbonyl moiety. In some embodiments,R^(Z7) and R^(Z8), where present, are taken together with the carbon towhich they are attached to form a carbonyl moiety.

In some embodiments, the compound is of the formula (I), or a saltthereof, where R^(Z) is hydrogen, or substituted or unsubstituted C₁-C₆alkyl. In one variation, R^(Z) is hydrogen. In another variation, R^(Z)is substituted or unsubstituted C₁-C₆ alkyl. In one such variation,R^(Z) is unsubstituted C₁-C₆ alkyl (e.g., methyl).

It is intended and understood that each and every variation of m, n,R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) andR^(Z8), where present, described for the formula (I) may be combinedwith each and every variation of j, k, R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10), where present,and/or each and every variation of X, R^(D), D and E described for theformula (I) as if each and every combination is individually described.For example, in some embodiments, provided is a compound of the formula(I), or a salt thereof, where each j and k is 0, R^(A1), R^(A2), R^(A3),R^(A4), R^(A5) and R^(A6) are as described herein, m is 1, n is 0, andR^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5) and R^(Z6) are asdescribed herein. In one variation, j and k are each 0, R^(A1), R^(A2),R^(A3), R^(A4), R^(A5) and R^(A6) are each hydrogen, m is 1, n is 0, andR^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5) and R^(Z6) are eachhydrogen.

In some embodiments, the compound is of the formula (I), or a saltthereof, where X is O. In some embodiments, the compound is of theformula (I), or a salt thereof, where X is S. In some of theseembodiments, R^(D) is hydrogen. In some of these embodiments, R^(D) issubstituted or unsubstituted C₁-C₆ alkyl. In one variation, X is O andR^(D) is hydrogen. In another variation, X is S and R^(D) is hydrogen.In another variation, X is O and R^(D) is unsubstituted C₁-C₆ alkyl(e.g., methyl). In some of these embodiments, D is hydrogen. In some ofthese embodiments, D is substituted or unsubstituted C₁-C₆ alkyl. Insome of these embodiments, D is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, or substituted or unsubstituted heterocyclyl. In someof these embodiments, D and R^(D) are independently H or substituted orunsubstituted C₁-C₆ alkyl (e.g., methyl). In some of these embodiments,D and R^(D) are taken together with the nitrogen to which they areattached to form a substituted or unsubstituted heterocyclyl (e.g.,3-methylazetidin-1-yl, 3-aminoazetidin-1-yl, morpholin-4-yl, andpiperidin-1-yl).

In some embodiments, the compound is of the formula (I), or a saltthereof, where D is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,or substituted or unsubstituted heterocyclyl. In some of theseembodiments, D is substituted or unsubstituted aryl (e.g., phenyl). Insome of these embodiments, D is substituted or unsubstituted C₃-C₈cycloalkyl. In some of these embodiments, D is substituted orunsubstituted heterocyclyl, such as substituted or unsubstitutedpyrrolidin-3-yl, piperidin-4-yl or piperidin-3-yl (e.g.,1-(isopropyl)piperidin-3-yl and1-(2-amino-2-methylpropanoyl)piperidin-3-yl). In some of theseembodiments, D is substituted or unsubstituted heteroaryl. In somevariations, D is a substituted or unsubstituted 5-membered heteroaryl,such as substituted or unsubstituted thiazolyl (e.g., thiazole-2-yl and5-chlorothiazol-2-yl) or substituted or unsubstituted thiadiazolyl(e.g., 1,2,4-thiadiazol-5-yl). In some variations, D is a substituted orunsubstituted 6-membered heteroaryl which contains at least one annularnitrogen atom. In some variations, D is a 6-membered heteroarylcontaining one annular nitrogen atom. In some variations, D is asubstituted pyridyl, such as a halo-substituted pyridyl (e.g.,6-fluoro-3-pyridyl). In some variations, D is an unsubstituted pyridyl(e.g., 3-pyridyl). In some variations, D is a 6-membered heteroarylcontaining two annular nitrogen atoms. In some variations, D is asubstituted or unsubstituted pyrimidyl (e.g., pyrimid-5-yl). In somevariations, D is a substituted or unsubstituted pyrazinyl (e.g.,pyrazin-2-yl).

In some embodiments, the compound is of the formula (I), or a saltthereof, where D is substituted or unsubstituted C₁-C₆ alkyl. In some ofthese embodiments, D is unsubstituted C₁-C₆ alkyl (e.g., methyl). Insome of these embodiments, D is substituted C₁-C₆ alkyl. In somevariations, D is C₁-C₆ alkyl (e.g., methyl) substituted with substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted C₃-C₈ cycloalkyl, or substituted orunsubstituted heterocyclyl. In some variations D is C₁-C₆ alkyl (e.g.,methyl) substituted with substituted or unsubstituted heteroaryl, suchas substituted or unsubstituted oxazolyl (e.g., oxazol-2-yl),substituted or unsubstituted pyrazolyl (e.g., pyrazol-5-yl or1-methylpyrazol-5-yl), substituted or unsubstituted furanyl (e.g.,furan-2-yl), or substituted or unsubstituted thiazolyl (e.g.,thiazol-2-yl).

It is intended and understood that each and every variation of X, R^(D)and D described for the formula (I) may be combined with each and everyvariation of j, k, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6),R^(A7), R^(A8), R^(A9) and R^(A10) where present, and/or each and everyvariation of m, n, R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5),R^(Z6), R^(Z7) and R^(Z8), where present, described for the formula (I)as if each and every combinations individually described. For example,in some embodiments, provided is a compound of the formula (I), or asalt thereof, where each j and k is 0, R^(A1), R^(A2), R^(A3), R^(A4),R^(A5) and R^(A6) are as described herein, m is 1, n is 0, and R^(Z),R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5) and R^(Z6) are as describedherein, X is O, R^(D) is hydrogen, and D is as described herein. In onevariation, j and k are each 0, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5)and R^(A6) are each hydrogen, m is 1, n is 0, R^(Z), R^(Z1), R^(Z2),R^(Z3), R^(Z4), R^(Z5) and R^(Z6) are each hydrogen, X is O, R^(D) ishydrogen, and D is substituted pyridyl, such as a halo-substitutedpyridyl (e.g., 6-fluoro-3-pyridyl).

In some embodiments, D is:

or taken together with R^(D) and the nitrogen to which they are attachedto form:

In some embodiments, D is:

or taken together with R^(D) and the nitrogen to which they are attachedto form:

In some embodiments, the compound is of the formula (I), or a saltthereof, where E is substituted or unsubstituted heteroaryl. In some ofthese embodiments, E is a substituted or unsubstituted 5-memberedheteroaryl containing two annular nitrogen atoms. In some variations, Eis substituted or unsubstituted pyrazolyl. In some variations, E is a5-substituted pyrazol-3-yl, such as a 5-cycloalkyl-pyrazol-3-yl (e.g.,5-(cyclopropyl)pyrazol-3-yl, 5-(1-methylcyclopropyl)pyrazol-3-yl,5-(1-hydroxycyclopropyl)pyrazol-3-yl and 5-cyclopentylpyrazol-3-yl), a5-alkyl-pyrazol-3-yl (e.g., 5-(isopropyl)pyrazol-3-yl), or5-carbamoylpyrazol-3-yl; or a 3-substituted pyrazol-5-yl, such as a3-cycloalkyl-pyrazol-5-yl (e.g., 3-(cyclopropyl)pyrazol-5-yl,3-(1-methylcyclopropyl)pyrazol-5-yl,3-(1-hydroxycyclopropyl)pyrazol-5-yl and 3-cyclopentylpyrazol-5-yl), a3-alkyl-pyrazol-5-yl (e.g., 3-(isopropyl)pyrazol-5-yl), or3-carbamoylpyrazol-5-yl. In some variations, E is a 5-substitutedpyrazol-3-yl, such as 5-hydroxypyrazol-3-yl, a 5-alkyl-pyrazol-3-yl(e.g. 5-(2-hydroxypropan-2-yl)pyrazol-3-yl or5-(1-hydroxypropan-2-yl)pyrazol-3-yl) or a 5-cycloalkylpyrazol-3-yl(e.g. 5-(2-hydroxycyclopropyl)pyrazol-3-yl). In some variations, E is a1- and 5-substituted pyrazol-3-yl (e.g.1-hydroxy-5-isoproylpyrazol-3-yl). In some variations, E is a pyrazolyloxide, such as a 5-alkyl-pyrazol-3-yl (e.g. 5-(isopropyl)pyrazol-3-yl2-oxide). In some variations, E is substituted or unsubstitutedimidazolyl, such as a substituted imidazol-4-yl (e.g.,1-(isopropyl)imidazol-4-yl and 2-(isopropyl)imidazol-4-yl) or asubstituted imidazol-5-yl (e.g., 2-(isopropyl)imidazol-5-yl). In somevariations, E is a substituted 5-membered heteroaryl which contains oneannular nitrogen atom and one annular oxygen atom. In some variations, Eis a substituted or unsubstituted oxazolyl (e.g.,5-carbamoyloxzazol-2-yl) or a substituted or unsubstituted isoxazolyl(e.g., 3-(isopropyl)isoxazol-5-yl). In some variations, E is asubstituted 5-membered heteroaryl which contains one annular nitrogenatom and one annular sulfur atom. In some variations, E is a substitutedor unsubstituted thiazolyl (e.g., 5-carbamoylthiazol-2-yl).

In some embodiments, E is:

In some embodiments, E is:

It is intended and understood that each and every variation of Edescribed for the formula (I) may be combined with each and everyvariation of j, k, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6),R^(A7), R^(A8), R^(A9) and R^(A10) where present, and/or each and everyvariation of m, n, R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5),R^(Z6), R^(Z7) and R^(Z8), where present, and/or each and everyvariation of X, R^(D) and D described for the formula (I) as if each andevery combination is individually described. For example, in someembodiments, provided is a compound of the formula (I), or a saltthereof, where each j and k is 0, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5)and R^(A6) are as described herein, m is 1, n is 0, and R^(Z), R^(Z1),R^(Z2), R^(Z3), R^(Z4), R^(Z5) and R^(Z6) are as described herein, X isO, R^(D) is hydrogen, and D is as described herein. In one variation, jand k are each 0, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) areeach hydrogen, m is 1, n is 0, R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4),R^(Z5) and R^(Z6) are each hydrogen, X is O, R^(D) is hydrogen, D issubstituted pyridyl, such as a halo-substituted pyridyl (e.g.,6-fluoro-3-pyridyl), and E is substituted pyrazolyl (e.g.,5-(cyclopropyl)pyrazol-3-yl or 5-(isopropyl)pyrazol-3-yl).

In one embodiment, provided is a compound of the formula (I-A):

or a salt thereof, where D, E, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5),R^(A6), R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6), p, R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as described for the formula (I),or any variation thereof. It is intended and understood that each andevery variation of D, E, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6),R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5) and R^(Z6), and each andevery combination thereof described herein for the formula (I) apply tothe formula (I-A) as if each and every variation and combination areindividually described. For example, in some embodiments, provided is acompound of the formula (I-A), or a salt thereof, where each of R^(A1),R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) is independently hydrogen,substituted or unsubstituted C₁-C₆ alkyl, halo, substituted orunsubstituted C₃-C₈ cycloalkyl or is taken together with a geminalR^(A(1-6)) group and the carbon to which they are attached to form acarbonyl group, R^(Z) is hydrogen or C₁-C₆ alkyl (e.g., methyl), each ofR^(Z1), R^(Z2), R^(Z3) and R^(Z4) is hydrogen, R^(Z5) and R^(Z6) areindependently hydrogen, hydroxyl or —OR¹, D is substituted orunsubstituted pyridyl, substituted or unsubstituted pyrimidyl, orsubstituted or unsubstituted pyrazinyl (e.g., 6-fluoro-3-pyridyl,3-pyridyl, pyrimid-5-yl and pyrazin-2-yl), and E is substituted orunsubstituted pyrazolyl, substituted or unsubstituted isoxazolyl, orsubstituted or unsubstituted imidazolyl (e.g.,5-cyclopropylpyrazol-3-yl, 5-cyclopentylpyrazol-3-yl,5-(isopropyl)pyrazol-3-yl, 3-cyclopropylpyrazol-5-yl,3-cyclopentylpyrazol-5-yl, 3-(isopropyl)pyrazol-5-yl, and3-(isopropyl)isoxazol-5-yl). In one variation, R^(A1), R^(A2), R^(A3),R^(A4), R^(A5), R^(A6), R^(Z), R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5)and R^(Z6) are each hydrogen, D is substituted pyridyl, such as ahalo-substituted pyridyl (e.g., 6-fluoro-3-pyridyl), and E issubstituted pyrazolyl (e.g., 5-(cyclopropyl)pyrazol-3-yl or5-(isopropyl)pyrazol-3-yl).

In some embodiments, provided are compounds of the formulae (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk),(IIl), (IIm), (IIn), (IIo), (IIp), (IIq), (IIr), (IIs), (IIt), (IIu),(IIv) and (IIw):

or a salt thereof, where in each of (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), (IIm), (IIn), (IIo),(IIp), (IIq), (IIr), (IIs), (IIt), (IIu), (IIv) and (IIw), thesubstituents D, E, m, n, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6),R^(D), R^(Z), X, R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7)R^(Z8), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as described forFormula (I) or any applicable variation thereof. In some variations, Xis O and R^(D) is hydrogen.

In some embodiments, provided are compounds of the formula (IIIa),(IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj),(IIIk), (IIIl), (IIIm), (IIIn), (IIIo), (IIIp), (IIIq), (IIIr), (IIIs),(IIt), (IIIu), (IIIv) and (IIIw):

or a salt thereof, where in each of (IIIa), (IIIb), (IIIc), (IIId),(IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), (IIIl), (IIIm),(IIIn), (IIIo), (IIIp), (IIIq), (IIIr), (IIIs), (IIt), (IIIu), (IIIv)and (IIIw), the substituents D, E, j, k, R^(A1), R^(A2), R^(A3), R^(A4),R^(A5), R^(A6), R^(D), R^(Z), X, R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5),R^(Z6), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as described forFormula (I) or any applicable variation thereof. In some variations, Xis O and R^(D) is hydrogen.

In some embodiments, provided are compounds of the formula (IVa),(IVa′), (IVb), (IVb′), (IVc), (IVc′), (IVd), (IVd′), (IVe), (IVe′),(IVf), (IVf′), (IVf″), (IVf′″), (IVg), (IVg′), (IVg″), (IVg′″), (IVh),(IVh′), (IVh″), (IVh′″), (IVi), (IVi′), (IVi″), (IVi′″), (IVj), (IVj′),(IVk), (IVk′), (IVl), (IVl′), (IVl″), (IVl′″), (IVm), (IVm′), (IVm″),(IVm′″), (IVn), (IVn′), (IVn″), (IVn′″), (IVo), (IVo′), (IVp), (IVp′),(IVq), (IVq′), (IVr), (IVr′), (IVs), (IVs′), (IVs″), (IVs′″), (IVt),(IVt′), (IVt″), (IVt′″), (IVu), (IVu′), (IVv), (IVv′), (IVw), and(IVw′):

or a salt thereof, where in each of (IVa), (IVa′), (IVb), (IVb′), (IVc),(IVc′), (IVd), (IVd′), (IVe), (IVe′), (IVf), (IVf′), (IVf″), (IVf′″),(IVg), (IVg′), (IVg″), (IVg′″), (IVh), (IVh′), (IVh″), (IVh′″), (IVi),(IVi′), (IVi″), (IVi′″), (IVj), (IVj′), (IVk), (IVk′), (IVl), (IVl′),(IVl″), (IVl′″), (IVm), (IVm′), (IVm″), (IVm′″), (IVn), (IVn′), (IVn″),(IVn′″), (IVo), (IVo′), (IVp), (IVp′), (IVq), (IVq′), (IVr), (IVr′),(IVs), (IVs′), (IVs″), (IVs′), (IVt), (IVt′), (IVt″), (IVt′″), (IVu),(IVu′), (IVv), (IVv′), (IVw), and (IVw′), the substituents D, E, j, k,R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(D), R^(Z), X, R^(Z1),R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, and R⁹ are as described for Formula (I) or any applicable variationthereof. In some variations, X is O and R^(D) is hydrogen.

In some embodiments, provided are compounds of the formula (Va), (Vb),(Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn),(Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (Vx), (Vy), (Vz),(Vaa), (Vbb), (Vcc), (Vdd), (Vee), (Vff), (Vgg), and (Vhh):

or a salt thereof, where in each of (Va), (Vb), (Vc), (Vd), (Ve), (Vf),(Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr),(Vs), (Vt), (Vu), (Vv), (Vw), (Vx), (Vy), (Vz), (Vaa), (Vbb), (Vcc),(Vdd), (Vee), (Vff), (Vgg), and (Vhh), the substituents D, E, R^(A1),R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(D), R^(Z), X, R^(Z3), R^(Z4),R^(Z5), R^(Z6), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are asdescribed for Formula (I) or any applicable variation thereof. In somevariations, X is O and R^(D) is hydrogen.

In another embodiment, provided is a compound of the formula (I-A):

or a salt thereof, where D, E, R^(A1), R^(A3), R^(A5), R^(Z), R^(Z1),R^(Z3), R^(Z5), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are asdescribed for the formula (I), or any applicable variation thereof,provided that one or more of R^(A2), R^(A4), R^(A6), R^(Z2), R^(Z4) andR^(Z6) is hydroxy. In one variation, one of R^(A2), R^(A4) and R^(A6) ishydroxy and the remaining R^(A2), R^(A4), R^(A6), R^(Z2), R^(Z4) andR^(Z6) are other than hydroxy. In one variation, two of R^(A2), R^(A4)and R^(A6) are hydroxy. In one variation, one of R^(Z2), R^(Z4) andR^(Z6) is hydroxy and the remaining R^(A2), R^(A4), R^(A6), R^(Z2),R^(Z4) and R^(Z6) are other than hydroxy. In another variation, two ofR^(Z2), R^(Z4) and R^(Z6) are hydroxy. In another variation, at leastone of R^(A2), R^(A4) and R^(A6) is hydroxy and at least one of R^(Z2),R^(Z4) and R^(Z6) is hydroxy. In another variation, one of R^(A2),R^(A4) and R^(A6) is hydroxy and one of R^(Z2), R^(Z4) and R^(Z6) ishydroxy.

For In another embodiment, provided is a compound of the formula (I-B):

or a salt thereof, where D, E, R^(A1), R^(A3), R^(A5), R^(Z), R^(Z1),R^(Z3), R^(Z5), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are asdescribed for the formula (I), or any applicable variation thereof,provided that one or more of R^(A2), R^(A4), R^(A6), R^(Z2), R^(Z4) andR^(Z6) is hydroxy or —OR¹. In one such variation, one or more of R^(A2),R^(A4), R^(A6), R^(Z2), R^(Z4) and R^(Z6) is hydroxy or —OR¹ where R¹ isan unsubstituted C₁-C₆ alkyl. In one variation, one of R^(A2), R^(A4)and R^(A6) is hydroxy or —OR¹ and the remaining R^(A2), R^(A4), R^(A6),R^(Z2), R^(Z4) and R^(Z6) are other than hydroxy or —OR¹. In onevariation, two of R^(A2), R^(A4) and R^(A6) are hydroxy or —OR¹. In onevariation, one of R^(Z2), R^(Z4) and R^(Z6) is hydroxy or —OR¹ and theremaining R^(A2), R^(A4), R^(A6), R^(Z2), R^(Z4) and R^(Z6) are otherthan hydroxy or —OR¹. In another variation, two of R^(Z2), R^(Z4) andR^(Z6) are hydroxy or —OR¹. In another variation, at least one ofR^(A2), R^(A4) and R^(A6) is hydroxy or —OR¹ and at least one of R^(Z2),R^(Z4) and R^(Z6) is hydroxy or —OR¹. In another variation, one ofR^(A2), R^(A4) and R^(A6) is hydroxy or —OR¹ and one of R^(Z2), R^(Z4)and R^(Z6) is hydroxy or —OR¹. In any variation of formula (I-B), in oneaspect, at least one of R^(A2), R^(A4), R^(A6), R^(Z4) and R^(Z6) ishydroxy or —OR¹ where R¹ is an unsubstituted C₁-C₆ alkyl.

For compounds bearing one or more chiral centers, each uniquestereoisomer has a compound number bearing a suffix “a”, “b”, etc. Asexamples, racemic compound 1, bearing one chiral center, can be resolvedinto its individual enantiomers 1a and 1b.

Similarly, racemic compound 10, bearing two chiral centers, can beresolved into its individual diastereomers 10a, 10b, 10c and 10d.

Similarly, racemic compound 22, bearing two chiral centers, can beresolved into its individual diastereomers 22a, 22b, 22c and 22d.

Similarly, racemic compound 66, bearing three chiral centers, can beresolved into its individual diastereomers 66a, 66b, 66c, 66d, 66e, 66f,66g, and 66h.

Representative compounds of the invention, and their stereoisomers, arelisted in Table 1.

TABLE 1 Compound No. Structure Compound Name 1 (1a, 1b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide 2 (2a, 2b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)pyrrolidine-2-carboxamide 3 (3a, 3b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (pyridin-3-yl)pyrrolidine-2- carboxamide4 (4a, 4b)

1-(4-(5-cyclopentyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)pyrrolidine-2-carboxamide 5 (5a, 5b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)azetidine-2-carboxamide 6 (6a, 6b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydo-5H-cyclopenta[d]pyrimidin-2-yl)-N- (pyrazin-2-yl)pyrrolidine-2- carboxamide7 (7a, 7b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (pyrimidin-5-yl)pyrrolidine-2-carboxamide 8 (8a, 8b)

N-(6-fluoropyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 9 (9a,9b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)piperidine-2-carboxamide 10 (10a, 10b, 10c, 10d)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide 11 (11a, 11b, 11c, 11d)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide 12 (12a, 12b)

N-(6-fluoropyridin-3-yl)-1-(4-(3- isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 13(13a, 13b)

N-(6-fluoropyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2- yl)pyrrolidine-2-carboxamide 14 (14a,14b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6- fluoropyridin-3-yl)pyrrolidine-2-carboxamide 15 (15a, 15b)

1-(4-(5-cyclopentyl-1H-pyrazol-3- ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6- fluoropyridin-3-yl)pyrrolidine-2-carboxamide 16 (16a, 16b)

N-(6-fluoropyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)piperidine-2-carboxamide 17(17a, 17b)

1-(4-(5-cyclopentyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)piperidine-2-carboxamide 18 (18a, 18b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 19 (19a, 19b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- methylpyrrolidine-2-carboxamide 20 (20a,20b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N- dimethylpyrrolidine-2-carboxamide 21(21a, 21b, 21c, 21d)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide 22 (22a, 22b, 22c, 22d)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (pyrrolidin-3-yl)pyrrolidine-2-carboxamide 23 (23a, 23b)

(3-aminoazetidin-1-yl)(1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- yl)pyrrolidin-2-yl)methanone24 (24a, 24b)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (thiazol-2-yl)pyrrolidine-2- carboxamide25 (25a, 25b)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2- methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide 26 (26a, 26b, 26c, 26d)

1-(4-((5-isopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (piperidin-3-yl)pyrrolidine-2-carboxamide 27 (27a, 27b, 27c, 27d)

N-(1-(2-amino-2- methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 28 (28a, 28b,28c, 28d)

N-(5-chlorothiazol-2-yl)-1-(4-((5- cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide 29 (29a, 29b)

N-(6-aminopyridin-3-yl)-1-(4-((5- cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide30 (30a, 30b, 30c, 30d)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4- hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide 31 (31a, 31b, 31c, 31d)

1-(4-((5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2- carboxamide 32 (32a, 32b)

N-(6-fluoropyridin-3-yl)-1-(4-((5-(1- methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 33 (33a, 33b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide 34 (34a, 34b, 34c, 34d)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4- methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide 35 (35a, 35b, 35c, 35d)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2- carboxamide 36 (36a, 36b, 36c, 36d)

4-fluoro-N-(6-fluoropyridin-3-yl)-1- (4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 37 (37a, 37b)

4,4-difluoro-N-(6-fluoropyridin-3-yl)- 1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 38 (38a, 38b)

3-((2-(2-((6-fluoropyridin-3- yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)amino)-1H-pyrazole-5-carboxamide39 (39a, 39b)

N-(6-fluoropyridin-3-yl)-1-(4-((1- isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide40 (40a, 40b, 40c, 40d)

4-hydroxy-1-(4-((1-isopropyl-1H- imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2- carboxamide 41 (41a, 41b)

2-((2-(2-((6-fluoropyridin-3- yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)amino)oxazole-5-carboxamide 42(42a, 42b)

N-(6-fluoropyridin-3-yl)-1-(4-((5-(1- hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 43 (43a, 43b, 43c, 43d)

N-(6-fluoropyridin-3-yl)-4-hydroxy-1- (4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 44 (44a, 44b)

2-((2-(2-((6-fluoropyridin-3- yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)amino)thiazole-5-carboxamide 45(45a, 45b)

N-(6-fluoropyridin-3-yl)-1-(4-((2- isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide46 (46a, 46b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 47 (47a, 47b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 48 (48a, 48b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-5,7- dihydrospiro[cyclopenta[d]pyrimidine-6,1′-cyclopropan]-2-yl)pyrrolidine-2- carboxamide 49 (49a, 49b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 50 (50a, 50b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 51 (51a, 51b)

1-(6,6-difluoro-4-((5-isopropyl-1H- pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)pyrrolidine-2-carboxamide 52 (52a, 52b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-5,7- dihydrospiro[cyclopenta[d]pyrimidine-6,2′-oxiran]-2-yl)pyrrolidine-2- carboxamide 53 (53a, 53b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 54 (54a, 54b)

1-(4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 55 (55a, 55b)

N-(6-fluoropyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide 56 (56a, 56b)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol- 2-yl)pyrrolidine-2-carboxamide 57(57a, 57b)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N- (thiazol-2-yl)pyrrolidine-2- carboxamide58 (58a, 58b, 58c, 58d)

(((1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6- fluoropyridin-3-yl)carbamoyl)pyrrolidin-3- yl)oxy)methyl)phosphonic acid 59 (59a, 59b,59c, 59d)

1-(4-((5-cyclopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6- fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl isobutyrate 60 (60a, 60b)

2-fluoro-5-(1-(4-((5-isopropyl-1H- pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamido)pyridine 1-oxide61 (61, 61b)

2-(2-((6-fluoropyridin-3- yl)carbamoyl)pyrrolidin-2-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide 62 (62a, 62b)

2-(2-((6-fluoropyridin-3- yl)carbamoyl)pyrrolidin-2-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-3-oxide 63 (63a, 63b)

N-(6-hydroxypyridin-3-yl)-1-(4-((5- isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide64 (64a, 64b)

1-(4-((5-isopropyl-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide 65 (65a, 65b, 65c, 65d)

1-(5-hydroxy-4-((5-isopropyl-1H- pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- hydroxypyridin-3-yl)pyrrolidine-2-carboxamide 66 (66a, 66b, 66c, 66d, 66e, 66f, 66g, 66h)

1-(5,7-dihydroxy-4-((5-isopropyl-1H- pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- hydroxypyridin-3-yl)pyrrolidine-2-carboxamide 67 (67a, 67b)

1-(4-((5-hydroxy-1H-pyrazol-3- yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- hydroxypyridin-3-yl)pyrrolidine-2-carboxamide 68 (68a, 68b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (thiazol-2-yl)pyrrolidine-2- carboxamide69 (69a, 69b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (pyrimidin-4-yl)pyrrolidine-2-carboxamide 70 (70a, 70b, 70c, 70d)

N-(6-fluoropyridin-3-yl)-4-hydroxy-1- (4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 71 (71a, 71b, 71c, 71d)

4-hydroxy-1-(4-(5-isopropyl-1H- pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (thiazol-2-yl)pyrrolidine-2- carboxamide72 (72a, 72b)

N-(6-aminopyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 73(73a, 73b)

(1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidin-2-yl)(piperidin-1- yl)methanone74 (74a, 74b)

(1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidin-2- yl)(morpholino)methanone 75(75a, 75b)

N-(6-fluoropyridin-3-yl)-1-(4-(5-(2- hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 76 (76a, 76b)

3-(2-(2-(6-fluoropyridin-3- ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- ylamino)-5-isopropyl-1H-pyrazole-2-oxide 77 (77a, 77b)

N-(6-fluoropyridin-3-yl)-1-(4-(1- hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 78 (78a, 78b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- (methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide 79 (79a, 79b)

N-(6-ethoxypyridin-3-yl)-1-(4-(5- isopropyl-1H-pyraozl-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 80(80a, 80b)

N-(6-fluoropyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)-4-oxopyrrolidine-2-carboxamide81 (81a, 81b, 81c, 81d)

N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 82(82a, 82b)

N-(2-hydroxyethyl)-1-(4-(5-isopropyl- 1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 83 (83a, 83b)

N-(6-fluoropyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carbothioamide 84(84a, 84b)

N-(2-fluoropyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 85(85a, 85b)

N-(furan-2-ylmethyl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 86(86a, 86b)

N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 87(87a, 87b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1- methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide 88 (88a, 88b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (oxazol-2-ylmethyl)pyrrolidine-2-carboxamide 89 (89a, 89b)

1-(4-(5-isopropyl-1H-pyrazol-3- ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N- (thiazol-2-ylmethyl)pyrrolidine-2-carboxamide 90 (90a, 90b, 90c, 90d)

N-(6-fluoropyridin-3-yl)-1-(4-(5-(1- hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 91 (91a, 91b, 91c, 91d)

N-(6-fluoropyridin-3-yl)-1-(4-(5-(2- hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 92 (92a, 92b, 92c, 92d)

1-(6-fluoro-4-(5-isopropyl-1H- pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6- fluoropyridin-3-yl)pyrrolidine-2-carboxamide 93 (93a, 93b 93c, 93d)

N-(6-fluoropyridin-3-yl)-1-(6- hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 94 (94a, 94b, 94c, 94d)

N-(6-fluoropyridin-3-yl)-1-(7- hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide 95 (95a, 95b)

N-(2-ethoxypyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)pyrrolidine-2-carboxamide 96(96a, 96b)

N-(6-fluoropyridin-3-yl)-1-(4-(5- isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)-N-methylpyrrolidine-2-carboxamide

It is understood that the Compound Name listed in Table 1 above refersto the racemic mixture of the compound. However, each of the compoundslisted in Table 1 may be resolved into the respective enantiomers and/ordiastereomers, if applicable, as shown by the compound numberdesignations a, b, c, d, etc. The compounds of the invention include thefollowing enantiomers and/or diastereomers, if applicable, in itsisomerically pure form or in a composition comprising mixtures ofcompounds of the invention in any ratio, including two or morestereochemical forms, such as in a racemic or non-racemic mixture or amixture of one or more diastereomers as listed in Table 1 or below:

-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;-   (2R,3R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (2S,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (2R,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (2S,3R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;-   (R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N-dimethylpyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N-dimethylpyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-(3-aminoazetidin-1-yl)(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)methanone;-   (S)-(3-aminoazetidin-1-yl)(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)methanone;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-piperidin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N—((R)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N—((S)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N—((S)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N—((R)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4S)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2R,4S)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (2S,4R)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;-   (R)—N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,2S)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,2S)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)-4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;-   (S)-3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;-   (R)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;-   (S)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;-   (S)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,1′-cyclopropan]-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,1′-cyclopropan]-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,2′-oxiran]-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,2′-oxiran]-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2S,4S)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2R,4S)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2S,4R)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonic    acid;-   (2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate;-   (2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate;-   (2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate;-   (2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl    isobutyrate-   (R)-2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine    1-oxide;-   (S)-2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine    1-oxide;-   (R)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    1-oxide;-   (S)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    1-oxide;-   (R)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    3-oxide;-   (S)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine    3-oxide;-   (R)—N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((R)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((S)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((S)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((R)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5R,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5R,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5S,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-((5S,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5R,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5R,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5S,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-((5S,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;-   (2R,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (2R,4R)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2R,4S)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;-   (2S,4S)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide-   (R)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone;-   (S)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone;-   (R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone;-   (S)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole    2-oxide;-   (S)-3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole    2-oxide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;-   (R,R)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;-   (R)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,R)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R,S)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S,R)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (S,S)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,R)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R,S)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,R)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S,S)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (R)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;-   (S)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide-   (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;    and-   (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide.    General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g., a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

Solvates and/or polymorphs of a compound provided herein or apharmaceutically acceptable salt thereof are also contemplated. Solvatescontain either stoichiometric or non-stoichiometric amounts of asolvent, and are often formed during the process of crystallization.Hydrates are formed when the solvent is water, or alcoholates are formedwhen the solvent is alcohol. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, and/or solubility. Various factorssuch as the recrystallization solvent, rate of crystallization, andstorage temperature may cause a single crystal form to dominate.

General Synthesis of Compounds of Formula (I)

Compounds of Formula (I) can be prepared according to the Scheme below.Appropriately functionalized beta-keto esters can be cyclized with ureato form dihydroxy pyrimidine products which, when subjected tochlorination conditions, yield the dichloropyrimidine derivatives.Treatment with appropriately functionalized amines E-NH₂, provide the4-amino-substituted pyrimidine which, upon reaction with variousamino-acid moieties give the 2,4-diaminopyrimidine compound. Conversionof the amino-acid moiety to an ester intermediate with Alkyl-OH reagentsis followed by reaction with an amine of the type DN(R^(D))H, yieldcompounds of Formula (I).

Beta-keto esters, such as, but not limited to, the following are eitheravailable or can be prepared by several routes known to those skilled inthe art:

Examples of “E-NH₂” such as, but not limited to, the following areeither available or can be synthesized by several routes known to thoseskilled in the art:

Numerous examples of cyclic amino-acids are available; typical examplesdiscussed herein include, but are not limited to, the following:

Examples of DN(R^(D))H are available; typical examples discussed hereininclude, but are not limited to, the following:

In one embodiment, the synthesis of compounds of Formula (v) isdescribed below.

In certain examples of formula (I) provided herein, and as similarlydescribed in the publications presented herein, compounds (i) to (v) canbe prepared by the steps as illustrated above.

Step-1 commences with appropriately functionalized cyclic β-keto esterswhich, if not commercially available, can be prepared according tomethods well-known in the art. As examples discussed herein, could besynthesized through routes shown below.

Treatment of the β-keto ester with urea under acidic conditions,followed by heating with base, results in the 5,6-cyclodihydroxypyrimidine. A number of synthetic protocols for preparingfunctionalized dihydroxypyrimidine compounds will be familiar to thoseskilled in the art. Conversion of the dihydroxypyrimidine in Step-2 tothe dichloropyrimidine derivative Compound (i) can be accomplished byheating with chlorinating reagents such as POCl₃ and SOCl₂.

Displacement of the chloro groups in dichloropyrimidine compoundstypically proceeds initially at the more labile 4-chloro position,followed by the 2-chloro position. As discussed herein, Compound (i) istreated initially with appropriately functionalized amino compounds suchas Compound (ii). Step-3 and Step-4 illustrate the preparation of afunctionalized amino pyrazole, by treatment of an ester withacetonitrile under basic conditions, followed by cyclization withhydrazine to give Compound (ii). Some examples of functionalizedpyrazoles can include for example:

Step-5 indicates that treatment of Compound (i) with Compound (ii) underbasic, polar conditions results in the 4-amino-substituted intermediateCompound (iii). A skilled person will be familiar with a range of bothbasic and acidic means for achieving this substitution. Whilefunctionalized pyrazoles have been illustrated above, otherfunctionalized amines can be considered such as amino-imidazoles,amino-thioimidazoles, amino-oxazoles, and the like.

Treatment of Compound (iii) with appropriately functionalized aminocompounds such as various amino acids, illustrated here with Proline inStep-6, provides the 2,4-diaminopyrimidine compound, which in Step-7 isconverted to the ester Compound (iv), under standard esterificationconditions. It is also possible that Step-7 could be by-passed,dependent upon the nature of the remainder of the molecular structureand whether direct conversion of the acid to the amide is achievablesynthetically, under standard amino acid coupling conditions with aminesto form amides. A number of alternative amino acids such asfunctionalized Proline compounds of the type illustrated here that arecommercially available, could be considered:

Step-8 completes the synthetic treatment of Compound (iv) withfunctionalized amines of the type R″—NH₂, typically under basicconditions known in the art for converting esters to amides, resultingin Compound (v). A large number of commercially available amines couldbe considered for this step, for illustration such as the following:

A skilled artisan will appreciate that the use of amino acids bearing achiral center in Step-6, and discussed in the Examples herein, willresult in stereoisomeric products that, dependent upon the appropriatechirality of the reagents and/or the conditions required to completeconversion of the intermediate compounds, will result in either singlestereoisomeric products, or mixtures of stereoisomers that may requirechiral separation by practical means known in the art. Step-9 indicatesthe separation of any stereoisomeric mixture of isomers of Compound (v),to yield the desired individual enantiomer or diastereomer, depending onthe number of stereocenters present.

In some embodiments, compounds of the formula (I) are synthesizedaccording to Scheme 1, following Steps 1-6 as described below. Thusprovided is also a process for making a compound of the formula (I)comprising steps 1-6. In each of 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,1.7a, 1.8, 1.8a, and 1.8b of Scheme 1, the substituents D, E, j, k, m,n, R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8),R^(A9), R^(A10), R^(D), R^(Z), X, R^(Z1), R^(Z2), R^(Z3), R^(Z4),R^(Z5), R^(Z6), R^(Z7), R^(Z8), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, andR⁹ are as described for Formula (I) or any applicable variation thereof.

Step-1: Synthesis of Compound 1.2

Compound 1.1 and urea are combined in a suitable solvent such as EtOH,cooled in an ice-bath, and concentrated HCl is added dropwise. Aftercompletion of the addition, the ice bath is removed and the reactionmixture stirred at RT for 30 min. The reaction mixture is then heated toreflux for 5 h. The reaction mixture is cooled to RT, and the EtOH wasdecanted to give a crystalline solid. The solid is heated to reflux withaqueous 5% NaOH solution for 2 h. The reaction mixture is cooled to RTand the precipitate collected by filtration. The precipitate is washedwith water and dried to afford compound 1.2.

Step-2: Synthesis of Compound 1.3

A suspension of compound 1.2 in POCl₃ is stirred at 100° C. for 3 h. Thereaction mixture is cooled to RT and poured slowly with constant shakinginto crushed ice to quench the excess of POCl₃. The aqueous layer isextracted with EtOAc. The combined organic layer is washed with waterand dried over anhydrous Na₂SO₄. Removal of EtOAc under reduced pressureaffords compound 1.3.

Step-3: Synthesis of Compound 1.4

N,N-diisopropylethyl amine is added to a solution of compound 1.3 inisopropanol followed by addition of compound E-NH₂ (5.89 g, 47 mmol).The reaction mixture is heated to reflux at 100° C. for 16 h. Thereaction mixture is cooled to RT. The precipitated product is filteredand washed with hexane to afford compound 1.4.

Step-4: Synthesis of Compound 1.6

Compound 1.5 is added to a suspension of compound 1.4 in dioxanefollowed by 5N NaOH and N,N-diisopropylethyl amine. The reaction mixtureis allowed to stir at 80° C. for 16 h. The solvent is removed underreduced pressure and the residue is acidified with 1 N HCl solution topH 4. The product is suspended in water, filtered, washed with ether anddried to afford compound 1.6.

Step-5: Synthesis of Compound 1.7

To a solution of 1.6 in MeOH (120 mL) is added HOBt.H₂O,N-methylmorpholine and EDC.HCl. The reaction mixture is stirred at RTovernight. The MeOH is removed under reduced pressure and the residue isdissolved in EtOAc. The solution is washed with water followed by brineand dried over anhydrous sodium sulfate. Removal of EtOAc under reducedpressure affords compound 1.7.

Step-6: Synthesis of Compound 1.8

To a solution of compound NHDR^(D) in dry THF is added a 2M solution ofisopropylmagnesium chloride in THF dropwise under nitrogen at 0° C. Theresultant mixture is stirred at 0° C. for 20 min. To this solution isadded a solution of 1.7 in THF (20 mL) dropwise at 0° C. and thereaction mixture is stirred at RT for 2 h. The reaction is quenched withsaturated ammonium chloride solution (50 mL). The product is extractedwith EtOAc and the organic layer is dried over anhydrous sodium sulfate.Removal of EtOAc under reduced pressure gives a solid residue that ispurified by column chromatography on silica gel using a 1-2% MeOH-DCMsystem as eluent to afford compound 1.8, followed by chiral purificationto afford enantiomers 1.8a and 1.8b.

Further Embodiments of the Invention

In one embodiment, the invention relates to Compounds described in Table1, and uses thereof.

In another embodiment, the invention relates to Compounds 1-59, andstereoisomers thereof, and uses thereof.

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable.

Representative examples of compounds detailed herein, includingintermediates and final compounds according to the invention aredepicted in the tables below. It is understood that in one aspect, anyof the compounds may be used in the methods detailed herein, including,where applicable, intermediate compounds that may be isolated andadministered to an individual. In some embodiments, embraced arecompounds of the formulae 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.7a, 1.8,1.8a, and 1.8b of Scheme 1, where D, E, j, k, m, n, R^(A1), R^(A2),R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8), R^(A9), R^(A10), R^(D),R^(Z), X, R^(Z1), R^(Z2), R^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7),R^(Z8), p, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹, where applicable, areas described for Formula (I) or any applicable variation thereof.

The compounds depicted herein may be present as salts even if salts arenot depicted and it is understood that the invention embraces all saltsand solvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan. In some embodiments, the salts of the compounds of theinvention are pharmaceutically acceptable salts. Where one or moretertiary amine moiety is present in the compound, the N-oxides are alsoprovided and described. For example, exemplary N-oxide compoundsinclude:

Where tautomeric forms may be present for any of the compounds describedherein, each and every tautomeric form is intended even though only oneor some of the tautomeric forms may be explicitly depicted. For example,when a 5-cyclopropyl-1H-pyrazol-3-yl moiety is depicted, thecorresponding 3-cyclopropyl-1H-pyrazol-5-yl tautomer is also intended.The tautomeric forms specifically depicted may or may not be thepredominant forms in solution or when used according to the methodsdescribed herein.

The invention also includes any or all of the stereochemical forms,including any enantiomeric or diastereomeric forms of the compoundsdescribed. The structure or name is intended to embrace all possiblestereoisomers of a compound depicted, and each unique stereoisomer has acompound number bearing a suffix “a”, “b”, etc. All forms of thecompounds are also embraced by the invention, such as crystalline ornon-crystalline forms of the compounds. Compositions comprising acompound of the invention are also intended, such as a composition ofsubstantially pure compound, including a specific stereochemical formthereof, or a composition comprising mixtures of compounds of theinvention in any ratio, including two or more stereochemical forms, suchas in a racemic or non-racemic mixture.

The invention also includes any or all metabolites of any of thecompounds described. The metabolites may include any chemical speciesgenerated by a biotransformation of any of the compounds described, suchas intermediates and products of metabolism of the compound. In additionto compounds described herein, those skilled in the art would appreciatethat typical metabolites of a compound such as, for example, CompoundNo. 8 could include, but are not limited to, the following:

Articles of manufacture comprising a compound of the invention, or asalt or solvate thereof, in a suitable container are provided. Thecontainer may be a vial, jar, ampoule, preloaded syringe, i.v. bag, andthe like.

Preferably, the compounds detailed herein are orally bioavailable.However, the compounds may also be formulated for parenteral (e.g.,intravenous) administration.

One or several compounds described herein can be used in the preparationof a medicament by combining the compound or compounds as an activeingredient with a pharmacologically acceptable carrier, which are knownin the art. Depending on the therapeutic form of the medication, thecarrier may be in various forms. In one variation, the manufacture of amedicament is for use in any of the methods disclosed herein, e.g., forthe treatment of cancer.

Pharmaceutical Compositions and Formulations

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. In onevariation, “substantially pure” intends a composition that contains nomore than 35% impurity, wherein the impurity denotes a compound otherthan the compound comprising the majority of the composition or a saltthereof. Taking compound 1 as an example, a composition of substantiallypure compound 1 intends a composition that contains no more than 35%impurity, wherein the impurity denotes a compound other than compound 1or a salt thereof. In one variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsno more than 25% impurity. In another variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 20% impurity. In still anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 10%impurity. In a further variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsor no more than 5% impurity. In another variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 3% impurity. In still anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 1%impurity. In a further variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsor no more than 0.5% impurity. In yet other variations, a composition ofsubstantially pure compound means that the composition contains no morethan 15% or preferably no more than 10% or more preferably no more than5% or even more preferably no more than 3% and most preferably no morethan 1% impurity, which impurity may be the compound in a differentstereochemical form. For instance, a composition of substantially pure(S) compound means that the composition contains no more than 15% or nomore than 10% or no more than 5% or no more than 3% or no more than 1%of the (R) form of the compound.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the invention embraces pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

The compound may be formulated for any available delivery route,including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal orrectal), parenteral (e.g., intramuscular, subcutaneous or intravenous),topical or transdermal delivery form. A compound may be formulated withsuitable carriers to provide delivery forms that include, but are notlimited to, tablets, caplets, capsules (such as hard gelatin capsules orsoft elastic gelatin capsules), cachets, troches, lozenges, gums,dispersions, suppositories, ointments, cataplasms (poultices), pastes,powders, dressings, creams, solutions, patches, aerosols (e.g., nasalspray or inhalers), gels, suspensions (e.g., aqueous or non-aqueousliquid suspensions, oil-in-water emulsions or water-in-oil liquidemulsions), solutions and elixirs.

One or several compounds described herein can be used in the preparationof a formulation, such as a pharmaceutical formulation, by combining thecompound or compounds as an active ingredient with a pharmaceuticallyacceptable carrier, such as those mentioned above. Depending on thetherapeutic form of the system (e.g., transdermal patch vs. oraltablet), the carrier may be in various forms. In addition,pharmaceutical formulations may contain preservatives, solubilizers,stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters,and salts for the adjustment of osmotic pressure, buffers, coatingagents or antioxidants. Formulations comprising the compound may alsocontain other substances which have valuable therapeutic properties.Pharmaceutical formulations may be prepared by known pharmaceuticalmethods. Suitable formulations can be found, e.g., in Remington'sPharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa.,20^(th) ed. (2000), which is incorporated herein by reference.

Compounds as described herein may be administered to individuals in aform of generally accepted oral compositions, such as tablets, coatedtablets, and gel capsules in a hard or in soft shell, emulsions orsuspensions. Examples of carriers, which may be used for the preparationof such compositions, are lactose, corn starch or its derivatives, talc,stearate or its salts, etc. Acceptable carriers for gel capsules withsoft shell are, for instance, plant oils, wax, fats, semisolid andliquid poly-ols, and so on. In addition, pharmaceutical formulations maycontain preservatives, solubilizers, stabilizers, re-wetting agents,emulgators, sweeteners, dyes, adjusters, and salts for the adjustment ofosmotic pressure, buffers, coating agents or antioxidants.

Any of the compounds described herein can be formulated in a tablet inany dosage form described, for example, a compound as described hereinor a pharmaceutically acceptable salt thereof can be formulated as a 10mg tablet.

Compositions comprising a compound provided herein are also described.In one variation, the composition comprises a compound and apharmaceutically acceptable carrier or excipient. In another variation,a composition of substantially pure compound is provided.

Methods of Use

Compounds and compositions of the invention, such as a pharmaceuticalcomposition containing a compound of any formula provided herein or asalt thereof and a pharmaceutically acceptable carrier or excipient, maybe used in methods of administration and treatment as provided herein.The compounds and compositions may also be used in in vitro methods,such as in vitro methods of administering a compound or composition tocells for screening purposes and/or for conducting quality controlassays.

In one aspect, the invention provides a method of inhibiting IGF-IRand/or IR comprising administering to an individual an effective amountof one or more compounds of the invention, or a salt thereof (e.g., apharmaceutically acceptable salt). In one aspect of the method, acompound of the invention or salt thereof inhibits binding of a ligandto the IGF-IR and/or IR receptor and/or reduces or eliminates orincreases or enhances or mimics an activity of the IGF-IR and/or IRreceptor in a reversible or irreversible manner. In some aspects, acompound of the invention inhibits binding of a ligand to the IGF-IRand/or IR receptor by at least about or by about any one of 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined by an assaydescribed herein. In some aspects, a compound of the invention reducesan activity of the IGF-IR and/or IR receptor by at least about or aboutany of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the receptor modulator or compared to the correspondingactivity in other subjects not receiving the compound. In one aspect,the individual has or is believed to have a disorder in which IGF-IRand/or IR is implicated. In some embodiments, the compound or saltthereof inhibits IGF-IR. In some embodiments, the compound or saltthereof inhibits IR. In certain embodiments, the compound or saltthereof inhibits both IGF-IR and IR. In certain variations, a compoundor composition of the invention is used to treat or prevent an IGF-IRand/or IR related disorder, such as cancer. In one aspect, the methodcomprises administering to the individual a compound provided herein, ora pharmaceutically acceptable salt thereof, including but not limited toa compound of the invention such as a compound according to any one ormore of formulae I; I-A; IIa-IIw; IIIa-IIIw; IVa-IVw; and Va-Vhh; or acompound of Table 1 or an isomer thereof, or a salt (such as apharmaceutically acceptable salt) of any of the foregoing. In oneaspect, the individual is a human in need of cancer treatment.

Unless clearly indicated otherwise, the term “individual” as used hereinrefers to a mammal, including but not limited to, bovine, horse, feline,rabbit, canine, rodent, or primate (e.g., human). In some embodiments,an individual is a human. In some embodiments, an individual is anon-human primate such as chimpanzees and other apes and monkey species.In some embodiments, an individual is a farm animal such as cattle,horses, sheep, goats and swine; pets such as rabbits, dogs and cats;laboratory animals including rodents, such as rats, mice, and guineapigs; and the like. The invention may find use in both human medicineand in the veterinary context.

The invention additionally provides methods of inhibiting thephosphorylation of AKT comprising administering to an individual aneffective amount of one or more compounds of the invention, or a saltthereof. In some aspects of the method, a compound detailed hereininhibits the phosphorylation of AKT by at least about or by about anyone of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% asdetermined by an assay described herein. In some aspects, a compounddetailed herein inhibits the phosphorylation of AKT by at least about orabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the compound or compared to the corresponding activity inother subjects not receiving the compound. In one aspect, the individualhas or is believed to have a disorder in which AKT phosphorylation isimplicated. In certain variations, inhibiting the phosphorylation of AKTis used to treat or prevent a disorder in which AKT phosphorylation isimplicated, such as cancer. In one aspect, the method comprisesadministering to the individual a compound provided herein, or apharmaceutically acceptable salt thereof, including but not limited to acompound of the invention such as a compound according to any one ormore of formulae I; I-A; IIa-IIw; IIIa-IIIw; IVa-IVw; and Va-Vhh; or acompound of Table 1 or an isomer thereof, or a salt (such as apharmaceutically acceptable salt) of any of the foregoing.

The invention also provides methods for modulating the activity of aprotein kinase comprising administering an effective amount of one ormore compounds of the invention, or a salt thereof, to an individual. Inone aspect, a method of modulating a protein kinase selected from thekinases of Tables B7-B13 are provided. In some embodiments, the proteinkinase comprises one or more protein serine/threonine kinases or one ormore protein tyrosine kinases. In some embodiments, the protein kinasecomprises one or more protein kinase provided in the accompanyingExamples, e.g., one or more protein kinase of Example B3. In someembodiments, the protein tyrosine kinase is selected from the groupconsisting of IGF-IR, IR, AXL, FAK2, Mer, Met, TrkB, and TrkC. In someembodiments, the protein serine/threonine kinase is selected from thegroup consisting of AURA, AURB, and AURC. In one aspect, the methodcomprises administering to the individual a compound provided herein, ora pharmaceutically acceptable salt thereof, including but not limited toa compound of the invention such as a compound according to any one ormore of formulae I; I-A; IIa-IIw; IIIa-IIIw; IVa-IVw; and Va-Vhh; or acompound of Table 1 or an isomer thereof, or a salt (such as apharmaceutically acceptable salt) of any of the foregoing.

The invention additionally provides methods for treating cancer in anindividual (e.g., human) comprising administering to the individual aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof or a composition comprising the compound or saltthereof. In one aspect, the method comprises administering to theindividual a compound provided herein, or a pharmaceutically acceptablesalt thereof, including but not limited to a compound of the inventionsuch as a compound according to any one or more of formulae I; I-A;IIa-IIw; IIIa-IIIw; IVa-IVw; and Va-Vhh; or a compound of Table 1 or anisomer thereof, or a salt (such as a pharmaceutically acceptable salt)of any of the foregoing. TrkC and the members of the TAM family ofreceptor tyrosine kinases (AXL, Mer and Met) have been widely implicatedin tumorigenesis and progression of several cancers and proposed astherapeutic targets for the treatment of prostate, breast, lung, renal,pancreatic cancers, neuroblastoma, medulloblastoma, head and neckcarcinoma and acute myeloid leukemia. In contrast, inhibition of aurorakinase family members AURA, AURB and AURC has been associated withadverse effects like grade 3 neutropenia, a significant drop in thewhite blood cell count. The invention also provides methods formodulating selectively the activity of protein tyrosine kinase receptorsof IGF-IR, IR, AXL, FAK2, Mer, Met, TrkB, and TrkC with lower levels orabsence of inhibition of members of Aurora kinase family. The inventionalso provides methods for preventing, and/or delaying the onset and/ordevelopment of cancer in an individual (e.g., human) comprisingadministering to the individual an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof or a compositioncomprising the compound or salt thereof.

In one variation, a method of treating cancer in an individual (e.g.,human) is provided comprising administering to the individual aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof, wherein the cancer is dependent on a kinasesignaling pathway (e.g., a signaling pathway of any of the kinases ofTables B7-B13). In one variation, a method of treating cancer in anindividual (e.g., human) is provided comprising administering to theindividual an effective amount of a compound of the invention or apharmaceutically acceptable salt thereof, wherein the cancer isdependent on the IGF-IR signaling pathway. In another variation, amethod of treating cancer in an individual (e.g., human) is providedcomprising administering to the individual an effective amount of acompound of the invention or a pharmaceutically acceptable salt thereof,wherein the cancer is characterized by depending on IGF-IR signaling forsurvival and/or proliferation. In yet another variation, a method oftreating cancer in an individual (e.g., human) is provided comprisingadministering to the individual an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof, wherein thecancer cells overexpress IGF-IR as compared to non-cancerous cells,e.g., as compared to non-cancerous cells of the same cell type.

In some embodiments, the amount of the compound or pharmaceuticallyacceptable salt thereof that is administered to an individual is anamount sufficient to decrease the size of a tumor, decrease the numberof cancer cells, or decrease the growth rate of a tumor by at leastabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%compared to the corresponding tumor size, number of cancer cells, ortumor growth rate in the same subject prior to treatment or compared tothe corresponding activity in other subjects not receiving thetreatment. Standard methods can be used to measure the magnitude of thiseffect, such as in vitro assays with purified enzyme, cell-based assays,animal models, or human testing.

In some embodiments, the cancer that may be treated is a solid tumorsuch as sarcomas and carcinomas. In some embodiments, the cancer thatmay be treated is a liquid tumor such as leukemia. Examples of cancersthat may be treated by methods of the invention include, but are notlimited to, breast cancer, prostate cancer, ovarian cancer, lung cancer,colon cancer, brain tumors, gastric cancer, liver cancer, thyroidcancer, endometrial cancer, gallbladder cancer, kidney cancer,adrenocortical cancer, sarcoma, skin cancer, head and neck cancer,leukemia, bladder cancer, colorectal cancer, hematopoietic cancer andpancreatic cancer. In some embodiments, the breast cancer is breastcarcinoma (ER negative or ER positive), primary breast ductal carcinoma,mammary adenocarcinoma, mammary ductal carcinoma (ER positive, ERnegative or HER2 positive), HER2 positive breast cancer, luminal breastcancer or triple negative breast cancer (TNBC). In some embodiments, thebreast cancer is unclassified. In some embodiments, the triple negativebreast cancer is a basal-like TNBC, a mesenchymal TNBC (mesenchymal ormesenchymal stem-like), an immunomodulatory TNBC, or a luminal androgenreceptor TNBC. In some embodiments, the prostate cancer is prostateadenocarcinoma. In some embodiments, the ovarian cancer is ovaryadenocarcinoma. In some embodiments, the lung cancer is lung carcinoma,non-small lung carcinoma, adenocarcinoma, mucoepidermoid, anaplastic,large cell, or unclassified. In some embodiments, the colon cancer iscolon adenocarcinoma, colon adenocarcinoma from a metastatic site lymphnode, metastatic colorectal cancer, or colon carcinoma. In someembodiments, a brain tumor is glioblastoma, astrocytoma, meduloblastoma,meningioma or neuroblastoma. In some embodiments, gastric cancer isstomach cancer. In some embodiments, liver cancer is hepatocellularcarcinoma, hepatoblastoma or cholangiocarcinoma. In some embodiments,liver cancer is hepatitis B virus-derived. In some embodiments, livercancer is virus negative. In some embodiments, thyroid cancer ispapillary thyroid carcinoma, follicular thyroid cancer or medullarythyroid cancer. In some embodiments, endometrial cancer is high gradeendometroid cancer, uterine papillary serous carcinoma or uterine clearcell carcinoma. In some embodiments, gallbladder cancer is gallbladderadenocarcinoma or squamous cell gallbladder carcinoma. In someembodiments, kidney cancer is renal cell carcinoma or urothelial cellcarcinoma. In some embodiments, adrenocortical cancer is adrenalcortical carcinoma. In some embodiments, sarcoma is synovial sarcoma,osteosarcoma, rhabdomiosarcoma, fibrosarcoma or Ewing's sarcoma. In someembodiments, skin cancer is basal cell carcinoma, squamous carcinoma ormelanoma. In some embodiments, head and neck cancer is oropharyngealcancer, nasopharyngeal cancer, laryngeal cancer and cancer of thetrachea. In some embodiments, the leukemia is acute promyelocyticleukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, mantle cell lymphoma or multiple myeloma.In some embodiments, the leukemia is acute promyelocytic leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, mantle cell lymphoma or multiple myeloma.

The invention additionally provides a method for treating a tumorcomprising contacting the tumor with an effective amount of one or morecompounds of the invention, or a salt thereof. In one aspect of themethod, a compound or salt thereof is administered to an individual inneed of tumor treatment. Exemplary tumors are derived from carcinomas ofthe breast, prostate, ovary, lung, or colon. In one aspect, thetreatment results in a reduction of the tumor size. In another aspect,the treatment slows or prevents tumor growth and/or metastasis.

The invention further provides methods for treating a hematopoieticmalignancy comprising administering an effective amount of one or morecompounds of the invention to an individual in need thereof. In someembodiments, the hematopoietic malignancy is acute promyelocyticleukemia.

Any of the methods of treatment provided herein may be used to treat aprimary tumor. Any of the methods of treatment provided herein may alsobe used to treat a metastatic cancer (that is, cancer that hasmetastasized from the primary tumor). Any of the methods of treatmentprovided herein may be used to treat cancer at an advanced stage. Any ofthe methods of treatment provided herein may be used to treat cancer ata locally advanced stage. Any of the methods of treatment providedherein may be used to treat early stage cancer. Any of the methods oftreatment provided herein may be used to treat cancer in remission. Insome of the embodiments of any of the methods of treatment providedherein, the cancer has reoccurred after remission. In some embodimentsof any of the methods of treatment provided herein, the cancer isprogressive cancer.

Any of the methods of treatment provided herein may be used to treat anindividual (e.g., human) who has been diagnosed with or is suspected ofhaving cancer. In some embodiments, the individual may be a human whoexhibits one or more symptoms associated with cancer. In someembodiments, the individual may have advanced disease or a lesser extentof disease, such as low tumor burden. In some embodiments, theindividual is at an early stage of a cancer. In some embodiments, theindividual is at an advanced stage of cancer. In some of the embodimentsof any of the methods of treatment provided herein, the individual maybe a human who is genetically or otherwise predisposed (e.g., has one ormore so-called risk factors) to developing cancer who has or has notbeen diagnosed with cancer. In some embodiments, these risk factorsinclude, but are not limited to, age, sex, race, diet, history ofprevious disease, presence of precursor disease, genetic (e.g.,hereditary) considerations, and environmental exposure. In someembodiments, the individuals at risk for cancer include, e.g., thosehaving relatives who have experienced this disease, and those whose riskis determined by analysis of genetic or biochemical markers. In someembodiments, the individual does not have type I diabetes. In someembodiments, the individual does not have type II diabetes withsustained hyperglycemia or type II diabetes with hyperglycemia forprolonged duration (e.g., for several years).

Any of the methods of treatment provided herein may be practiced in anadjuvant setting. In some embodiments, any of the methods of treatmentprovided herein may be used to treat an individual who has previouslybeen treated for cancer, e.g., with one or more other therapies such asradiation, surgery or chemotherapy. Any of the methods of treatmentprovided herein may be used to treat an individual who has notpreviously been treated for cancer. Any of the methods of treatmentprovided herein may be used to treat an individual at risk fordeveloping cancer, but who has not been diagnosed with cancer. Any ofthe methods of treatment provided herein may be used as a first linetherapy. Any of the methods of treatment provided herein may be used asa second line therapy.

Any of the methods of treatment provided herein in one aspect reduce theseverity of one or more symptoms associated with cancer by at leastabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%compared to the corresponding symptom in the same subject prior totreatment or compared to the corresponding symptom in other subjects notreceiving a compound or composition of the invention.

Any of the methods of treatment provided herein may be used to treat,stabilize, prevent, and/or delay any type or stage of cancer. In someembodiments, the individual is at least about any of 40, 45, 50, 55, 60,65, 70, 75, 80, or 85 years old. In some embodiments, one or moresymptoms of the cancer are ameliorated or eliminated. In someembodiments, the size of a tumor, the number of cancer cells, or thegrowth rate of a tumor decreases by at least about any of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, thecancer is delayed or prevented.

In some embodiments, a compound or composition of the invention may beused to treat or prevent cancer in conjunction with a second therapyuseful to reduce one or more side effects associated with administeringthe compound or composition of the invention. In some embodiments, thesecond compound for such combination therapy is selected from agentsused for the treatment of glucose-related disorders such as Type 2diabetes mellitus, impaired glucose tolerance, Insulin ResistanceSyndrome and hyperglycemia. Examples of such agents include oralantidiabetic compounds from the classes of sulfonylureas, biguanides,thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, otherinsulin-sensitizing compounds and/or other antidiabetic agents.Particular examples comprise Metformin (N,N-dimethylimidodicarbonimidicdiamide), sulfonylureas and the like, or a salt of the forgoing. Testingof glucose concentration levels in an individual receiving a compound ofthe present invention may be followed by the co-administration of such asecond agent (e.g., Metformin) as part of a combination therapy whereappropriate (e.g., where the results of a glucose concentration leveltest in an individual indicate that such combination therapy will be oris expected to be beneficial for the individual).

In some embodiments, the compounds and compositions of the invention maybe used to treat or prevent cancer in conjunction with a second therapyuseful for cancer treatment. The second therapy includes, but is notlimited to, surgery, radiation, and/or chemotherapy.

Dosing and Method of Administration

The dose of a compound administered to an individual (such as a human)may vary with the particular compound or salt thereof, the method ofadministration, and the particular stage of cancer being treated. Theamount should be sufficient to produce a desirable response, such as atherapeutic or prophylactic response against cancer. In someembodiments, the amount of the compound or salt thereof is atherapeutically effective amount. In some embodiments, the amount of thecompound or salt thereof is a prophylactically effective amount. In someembodiments, the amount of compound or salt thereof is below the levelthat induces a toxicological effect (e.g., an effect above a clinicallyacceptable level of toxicity) or is at a level where a potential sideeffect can be controlled or tolerated when the composition isadministered to the individual.

In some embodiments, the amount of compound or salt thereof is an amountsufficient to inhibit IGR-IR and/or IR, inhibit the phosphorylation ofAKT, inhibit cancer cell growth and/or proliferation or increaseapoptosis of cancer cells.

The effective amount of the compound may in one aspect be a dose ofbetween about 0.01 and about 100 mg/kg.

Any of the methods provided herein may in one aspect compriseadministering to an individual a pharmaceutical composition thatcontains an effective amount of a compound provided herein or a saltthereof and a pharmaceutically acceptable excipient.

A compound or composition of the invention may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer, which in some variations may be for theduration of the individual's life. In one variation, the compound isadministered on a daily or intermittent schedule. The compound can beadministered to an individual continuously (for example, at least oncedaily) over a period of time. The dosing frequency can also be less thanonce daily, e.g., about a once weekly dosing. The dosing frequency canbe more than once daily, e.g., twice or three times daily. The dosingfrequency can also be intermittent, including a ‘drug holiday’ (e.g.,once daily dosing for 7 days followed by no doses for 7 days, repeatedfor any 14 day time period, such as about 2 months, about 4 months,about 6 months or more). Any of the dosing frequencies can employ any ofthe compounds described herein together with any of the dosagesdescribed herein.

The compounds provided herein or a salt thereof may be administered toan individual via various routes, including, e.g., intravenous,intramuscular, subcutaneous, oral and transdermal. A compound providedherein can be administered frequently at low doses, known as ‘metronomictherapy,’ or as part of a maintenance therapy using compound alone or incombination with one or more additional drugs. Metronomic therapy ormaintenance therapy can comprise administration of a compound providedherein in cycles. Metronomic therapy or maintenance therapy can compriseintra-tumoral administration of a compound provided herein.

In one aspect, the invention provides a method of treating cancer in anindividual by parenterally administering to the individual (e.g., ahuman) an effective amount of a compound or salt thereof. In someembodiments, the route of administration is intravenous, intra-arterial,intramuscular, or subcutaneous. In some embodiments, the route ofadministration is oral. In still other embodiments, the route ofadministration is transdermal.

The invention also provides compositions (including pharmaceuticalcompositions) as described herein for the use in treating, preventing,and/or delaying the onset and/or development of cancer and other methodsdescribed herein. In certain embodiments, the composition comprises apharmaceutical formulation which is present in a unit dosage form.

Also provided are articles of manufacture comprising a compound of theinvention or a salt thereof, composition, and unit dosages describedherein in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. Anarticle of manufacture may further be sterilized and/or sealed.

Kits

The invention further provides kits for carrying out the methods of theinvention, which comprises one or more compounds described herein or apharmacological composition comprising a compound described herein. Thekits may employ any of the compounds disclosed herein. In one variation,the kit employs a compound described herein or a pharmaceuticallyacceptable salt thereof. The kits may be used for any one or more of theuses described herein, and, accordingly, may contain instructions forthe treatment of cancer.

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit.

The kits may be in unit dosage forms, bulk packages (e.g., multi-dosepackages) or subunit doses. For example, kits may be provided thatcontain sufficient dosages of a compound as disclosed herein and/or asecond pharmaceutically active compound useful for a disease detailedherein (e.g., hypertension) to provide effective treatment of anindividual for an extended period, such as any of a week, 2 weeks, 3weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7months, 8 months, 9 months, or more. Kits may also include multiple unitdoses of the compounds and instructions for use and be packaged inquantities sufficient for storage and use in pharmacies (e.g., hospitalpharmacies and compounding pharmacies).

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present invention. Theinstructions included with the kit generally include information as tothe components and their administration to an individual.

EXAMPLES

The following Examples are provided to illustrate but not to limit theinvention.

General Protocol for Chiral Preparative HPLC Separation of RacemicCompounds

For chiral separations, samples were dissolved in MeOH and EtOHaccording to the solubility of sample and filtered through 0.22μ PTFEfilters. The columns used were CHIRALPAK-AD; 20*250 mm, 10μ andCHIRALCEL-ODH; 20*250 mm, 5μ. A flow rate of 12 mL/min-17 mL/min wasused according to the resolution. Alkanes such as n-Pentane, Hexane andHeptane (40%-95%) and alcohols such as EtOH, Isopropyl alcohol andt-Butanol (5%-60%) were used as mobile phase. In some cases alcoholcombinations i.e. (EtOH+MeOH), (EtOH+IPA), (IPA+MeOH), (t-Butanol+MeOH),(t-Butanol+EtOH) were used instead of a single alcohol. Diethyl amine(up to 0.3%) was used as modifier in the mobile phase.

Example H1 General Method for the Chiral HPLC Separation andCharacterization of Compounds that are Synthesized Initially as aMixture of Enantiomers

Crude or in some cases partially purified (normal or reverse phase HPLC)mixtures of enantiomers are analyzed by analytical chiral HPLC methods.Once adequate separation is achieved, larger quantities of the mixturesare separated using preparative scale columns. Separation is followed byremoval of solvents on a rotary evaporator to accomplish the isolationof the individual single enantiomers. In some cases where appropriate,after removal of solvent, the samples are lyophilized. After isolation,each individual enantiomer is further analyzed by analytical (reversephase and chiral) HPLC, LCMS and NMR. When final products are convertedto salts, final characterization of the compounds is carried out afterconversion to the salt for each enantiomer.

Analytical Chiral HPLC of Compounds of the Invention.

Column: Chiralcel OD-H; Column ID: 4.6*250 mm, 5μ. Mobile Phase:Hexane:(EtOH:MeOH 80:20)-93:7. Flow rate: 1 mL/min.

Chiral Preparative Data of Compounds of the Invention.

Column: Chiralcel OD-H. Column ID: 20*250 mm, 5μ. Mobile Phase: Hexane:(EtOH:MeOH 80:20)-95:5. Flow rate: 15 mL/min.

Example H2 General Method for the Chiral HPLC Separation andCharacterization of Compounds that are Synthesized Initially as aMixture of Diastereomers

Crude or in some cases partially purified (normal or reverse phase HPLC)mixtures of diastereomers are analyzed by analytical chiral HPLCmethods. Once adequate separation is achieved, larger quantities of themixtures are separated using preparative scale columns. Separation isfollowed by removal of solvents on a rotary evaporator to accomplish theisolation of the individual single diastereomers. In some cases whereappropriate, after removal of solvent, the samples are lyophilized. Onceeach individual diastereomer is isolated they are further analyzed byanalytical (reverse phase and chiral) HPLC, LCMS and NMR. When finalproducts are converted to salts, final characterization of the compoundsis carried out after conversion to the salt for each diastereomer.

Analytical Chiral HPLC Data of Compounds of the Invention.

Column: Chiral Pak AD-H. Column ID: 4.6*250 mm, 5μ. Mobile Phase: Hexane(0.2% diethylamine): Isopropanol—93:7. Flow rate: 1 mL/min.

Chiral Preparative Data of Compounds of the Invention.

Column: Chiral PAK-AD-H. Column ID: 20*250 mm, 5μ. Mobile Phase: Hexane(0.2% diethylamine): Isopropanol—93:7. Flow rate: 15 mL/min.

The following abbreviations are used herein: thin layer chromatography(TLC); hour (h); minute (min); second (sec); ethanol (EtOH);dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroaceticacid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol(MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor(Rf); room temperature (RT).

Compounds detailed herein may be prepared by those of skill in the artby referral to the General Method. Particular examples of the GeneralMethod are provided in the Examples below.

Example 1 Preparation of Compound (i)

Step-1: Synthesis of 6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol

To a suspension of ethyl 2-oxocyclopentanecarboxylate (10 mL, 67.2 mmol)and urea (6.07 g, 101 mmol) in EtOH (20 mL), cooled in an ice-bath, wasadded concentrated HCl (1 mL) dropwise. After completion of addition,the ice bath was removed and the reaction mixture was stirred at RT for30 min. The reaction mixture was then heated to reflux at 85° C. for 5h. The reaction mixture was cooled to RT and the EtOH was decanted togive a crystalline solid. The solid was heated to reflux with aqueous 5%NaOH solution (25 mL) for 2 h. The reaction mixture was cooled to RT andthe precipitate was collected by filtration. The precipitate was washedwith water and dried to afford6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (5.36 g, 52% yield). ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 1.81-1.97 (m, 2H), 2.38-2.46 (m, 2H),2.47-2.60 (m, 2H), 10.70 (s, 1H), 11.05 (s, 1H).

Step-2: Synthesis of2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, Compound (i)

A suspension of 6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (13 g,85.52 mmol) in POCl₃ (100 mL) was stirred at 100° C. for 3 h. Thereaction mixture was cooled to RT and poured slowly with constantshaking into crushed ice to quench the excess of POCl₃. The aqueouslayer was extracted with EtOAc (3×200 mL). The combined organic layerwas washed with water (8×300 mL) and dried over anhydrous Na₂SO₄.Removal of EtOAc under reduced pressure afforded2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, Compound (i) (13.0g, 81% yield). ¹HNMR (400 MHz, CDCl₃) δ (ppm): 2.17-2.25 (m, 2H),2.93-3.00 (m, 2H), 3.01-3.12 (m, 2H).

Example 2 Preparation of Compound (ii)

Step-1: Synthesis of 4-methyl-3-oxopentanenitrile

To a suspension of sodium hydride (11.40 g, 284 mmol) in THF (250 mL)was added acetonitrile (11.36 g, 278 mmol) slowly at 0° C. The reactionmixture was allowed to stir at RT for 20 min. The reaction mixture wasthen cooled to 0° C. and to it was added slowly a solution of methylisobutyrate (25 g, 245 mmol) in THF (50 mL). The reaction mixture washeated to reflux under nitrogen at 70° C. for 6 h. The solvent wasremoved under reduced pressure and the reaction mass was treated with1:1 water-DCM mixture (600 mL). The aqueous layer was acidified with 1NHCl and extracted with DCM (2×400 mL). The organic layer was dried overanhydrous sodium sulfate. Removal of solvent under reduced pressureafforded 4-methyl-3-oxopentanenitrile (15 g, 55% yield). ¹H NMR (400MHz, CDCl₃) δ (ppm): 1.18 (d, 6H), 2.72-2.84 (m, 1H), 3.51 (s, 2H).

Step-2: Synthesis of 5-isopropyl-1H-pyrazol-3-amine, Compound (ii)

To a solution of 4-methyl-3-oxopentanenitrile (15 g, 135 mmol) in EtOH(150 mL) was added hydrazine hydrate (7.30 g, 146 mmol) slowly at 0° C.The reaction mixture was heated to reflux for 4 h. Removal of EtOH underreduced pressure gave an oily residue that was dissolved in EtOAc (200mL) and washed with freshly prepared brine (2×50 mL). The organic layerwas dried over anhydrous sodium sulfate. Removal of EtOAc gave5-isopropyl-1H-pyrazol-3-amine, Compound (ii) (10 g, 59% yield). ¹H NMR(400 MHz, CDCl₃) δ (ppm): 1.22 (d, 6H), 2.80-2.92 (m, 1H), 4.80 (brs,3H), 5.41 (s, 1H).

Example 3 Preparation of Compound (iii)

Synthesis of2-chloro-N-(5-isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine,Compound (iii)

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine,Compound (i) (8 g, 42 mmol) in isopropanol (100 mL) was addedN,N-diisopropylethyl amine (8.67 g, 67 mmol) followed by5-isopropyl-1H-pyrazol-3-amine, Compound (ii) (5.89 g, 47 mmol). Thereaction mixture was heated to reflux at 100° C. for 16 h. The reactionmixture was cooled to RT. The precipitated product was filtered andwashed with hexane to afford2-chloro-N-(5-isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine,Compound (iii) (5 g, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 1.22 (d,6H), 1.96-2.07 (m, 2H), 2.70-2.81 (m, 4H), 2.88-3.01 (m, 1H), 6.38 (s,1H), 9.60 (s, 1H), 12.11 (brs, 1H).

Example 4 Preparation of Compound (iv)

Step-1: Synthesis of1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid

To a suspension of2-chloro-N-(5-isopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine,Compound (iii) (5 g, 18 mmol) in dioxane (60 mL) was added L-proline(3.11 g, 27 mmol) followed by 5N NaOH (5.4 mL, 27 mmol) andN,N-diisopropylethyl amine (2.32 g, 18 mmol). The reaction mixture wasallowed to stir at 100° C. for 16 h. The solvent was removed underreduced pressure and the residue was acidified with 1 N HCl solution topH 4. The product was suspended in water (10 mL), filtered, washed withether and dried to afford1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (5 g, 78% yield).

Step-2: Synthesis of methyl1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate,Compound (iv)

To a solution of1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (5 g, 14 mmol) in MeOH (120 mL) was added HOBt.H₂O (143 mg, 0.94mmol), N-methylmorpholine (1.42 g, 14 mmol) and EDC.HCl (3.64 g, 19mmol). The reaction mixture was stirred at RT overnight. The MeOH wasremoved under reduced pressure and the residue was dissolved in EtOAc(100 mL). The solution was washed with water (2×40 mL) followed by brine(40 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc underreduced pressure afforded methyl1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate,Compound (iv) (5 g, 96% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.30(d, 6H), 1.98-2.20 (m, 4H), 2.06-2.37 (m, 1H), 2.60-2.66 (m, 2H),2.67-2.2.88 (m, 2H), 2.90-3.07 (m, 1H), 3.65-3.79 (m, 1H), 3.70 (s, 3H),3.80-3.91 (m, 2H), 4.61-4.70 (m, 1H), 6.18 (s, 1H), 6.59 (s, 1H).

Example 5 Preparation of Compound Nos. 1, 1a and 1b

To a solution of(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylpyrrolidine-2-carboxylicacid (1.1 g, 2.99 mmol) in DMF (12 mL) was added 6-fluoropyridin-3-amine(1.7 g, 15.18 mmol), diisopropylethylamine (0.578 g, 4.48 mmol) and HBTU(1.13 g, 2.99 mmol) and the reaction mixture was stirred at RT for 16 h.The reaction mixture was diluted with water (200 mL) and extracted withEtOAc (3×100 mL). The combined organic layer was washed with water(9×200 mL) and dried over anhydrous sodium sulfate. Removal of solventunder reduced pressure gave a crude product which was purified byreverse phase HPLC to afford 50 mg of(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide.¹H NMR (400 MHz, CD₃OD, TFA salt) δ (ppm): 0.70-0.80 (m, 2H), 0.89-0.99(m, 2H), 1.77-1.83 (m, 1H), 1.80 (s, 3H), 2.16-2.30 (m, 5H), 2.38-2.43(m, 1H), 2.77-2.83 (m, 2H), 2.98-3.05 (m, 2H), 3.78-3.82 (m, 1H),3.88-3.98 (m, 1H), 6.02 (s, 1H), 6.99 (d, 1H), 7.82-7.90 (m, 1H), 8.18(s, 1H). The other enantiomer was prepared using the (R) chiral startingmaterial.

Example 6 Preparation of Compound Nos. 2, 2a and 2b

To a solution of 6-fluoropyridin-3-amine (6.09 g, 54.4 mmol) in dry THF(100 mL) was added a 2M solution of isopropylmagnesium chloride (27.2mL, 54.4 mmol) in THF dropwise under nitrogen at 0° C. The resultantmixture was stirred at 0° C. for 20 min. To this solution was added asolution of methyl1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(5 g, 13.5 mmol) in THF (20 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at RT for 2 h. The reaction was quenchedwith saturated ammonium chloride solution (200 mL). The product wasextracted with EtOAc (2×80 mL) and the organic layer was dried overanhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave asolid residue which was purified by column chromatography on silica gelusing 2-2.5% MeOH-DCM system as eluent to afford1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide(2.85 g, 47% yield) as the racemate. ¹H NMR (400 MHz, CD₃OD, freebase) δ(ppm): 0.56-0.72 (m, 2H), 0.82-0.94 (m, 2H), 1.70-1.82 (m, 1H),2.00-2.20 (m, 4H), 2.21-2.38 (m, 2H), 2.70-2.77 (m, 2H), 2.78-2.82 (m,2H), 3.58-3.78 (m, 1H), 3.79-3.81 (m, 1H), 4.70 (dd, 1H), 6.25 (s, 1H),6.98 (dd, 1H), 7.95 (s, 1H), 8.18 (s, 1H). Separation by chiral HPLCprovided enantiomers 2a and 2b.

Example 7 Preparation of Compound Nos. 3, 3a and 3b

To a solution of1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (200 mg, 0.566 mmol) in DMF (2 mL) was added 3-amino pyridine (265mg, 2.824 mmol), HATU (257 mg, 0.672 mmol) and DIPEA (0.166 mL, 0.902mmol). The reaction mixture was allowed to stir at RT for 16 h. Thereaction mixture was diluted with water (40 mL) and extracted with EtOAc(2×25 mL). The organic layer was washed with water (8×30 mL) and driedover anhydrous sodium sulfate. Removal of EtOAc under reduced pressuregave a crude product that was purified by reverse phase HPLC to afford1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide(25 mg) as racemate. The enantiomers were separated by chiral HPLC toafford(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide(10 mg). ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 0.56-0.70 (m, 2H),0.78-0.87 (m, 2H), 1.69-1.81 (m, 1H), 2.00-2.19 (m, 4H), 2.21-2.39 (m,2H), 2.68-2.81 (m, 4H), 3.58-3.72 (m, 1H), 3.78-3.89 (m, 1H), 4.65-4.78(m, 1H), 6.25 (s, 1H), 7.33 (dd, 1H), 7.94 (s, 1H), 8.22 (d, 1H), 8.60(s, 1H).

Example 8 Preparation of Compound Nos. 4, 4a and 4b

To a solution of 6-fluoropyridin-3-amine (565 mg, 5.044 mmol) in dry THF(20 mL) was added 2M solution of isopropylmagnesium chloride in THF (2.5mL, 5.044 mmol) dropwise under nitrogen at 0° C. The resultant mixturewas stirred at 0° C. for 20 min. To this solution was added a solutionof1-(4-(3-cyclopentyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(500 mg, 1.262 mmol) in THF (5 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at RT for 2 h. The reaction was quenchedwith saturated ammonium chloride solution (50 mL). The product wasextracted with EtOAc (2×60 mL) and the organic layer was dried overanhydrous sodium sulfate. Removal of EtOAc under reduced pressureafforded an oily residue that was purified by reverse phase HPLC toafford1-(4-(3-cyclopentyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamideas the formate salt (220 mg). ¹H NMR (400 MHz, CD₃OD, formate salt) δ(ppm): 1.41-1.80 (m, 6H), 1.81-2.00 (m, 2H), 2.07-2.21 (m, 4H),2.22-2.38 (m, 2H), 2.76-2.81 (m, 2H), 2.82-2.97 (m, 3H), 3.59-3.70 (m,1H), 3.77-3.86 (m, 1H), 4.70-4.80 (m, 1H), 6.27 (brs, 1H), 6.97 (dd,1H), 7.93-8.02 (m, 1H), 8.18 (s, 1H). Separation by chiral HPLC providedenantiomers 4a and 4b.

Example 9 Preparation of Compound Nos. 5, 5a and 5b

To a solution of(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)azetidine-2-carboxylicacid (300 mg, 0.909 mmol) in DMF (3 mL) was added6-fluoropyridin-3-amine (203 mg, 1.818 mmol), HATU (414 mg, 1.091 mmol)and DIPEA (0.26 mL, 1.45 mmol). The reaction mixture was allowed to stirat RT for 16 h. The reaction mixture was diluted with water (40 mL) andextracted with EtOAc (2×25 mL). The organic layer was washed with water(8×30 mL) and dried over anhydrous sodium sulfate. Removal of EtOAcunder reduced pressure gave a crude product that was purified by reversephase HPLC to afford 40 mg of(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamideas the formate salt. ¹H NMR (400 MHz, CD₃OD, TFA salt) δ (ppm):0.40-0.60 (m, 2H), 0.70-0.85 (m, 2H), 1.58-1.70 (m, 1H), 2.20-2.37 (m,2H), 2.58-2.69 (m, 1H), 2.79-2.97 (m, 3H), 2.98-3.06 (m, 2H), 4.21-4.38(2H), 5.16 (dd, 1H), 6.16 (s, 1H), 7.05 (dd, 1H), 8.05-8.17 (m, 1H),8.30 (s, 1H). The other enantiomer was prepared using the (R) chiralstarting material.

Example 10 Preparation of Compound Nos. 6, 6a and 6b

To a solution of pyrazin-2-amine (284 mg, 2.99 mmol) in dry THF (12 mL)was added 2M solution of isopropylmagnesium chloride (1.5 mL, 2.99 mmol)in THF dropwise under nitrogen at 0° C. The resultant mixture wasstirred at 0° C. for 20 min. To this solution was added a solution ofmethyl1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(200 mg, 0.746 mmol) in THF (2 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at RT for 1.5 h. The reaction was quenchedwith saturated ammonium chloride solution (20 mL). The product wasextracted with EtOAc (2×40 mL) and the organic layer was dried overanhydrous sodium sulfate. Removal of EtOAc under reduced pressureafforded an oily residue that was purified by reverse phase HPLC toafford1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide(120 mg). ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 0.57-0.67 (m, 2H),0.78-0.95 (m, 2H), 1.70-1.81 (m, 1H), 2.02-2.18 (m, 4H), 2.25-2.39 (m,2H), 2.63-2.78 (m, 2H), 2.79-2.85 (m, 2H), 3.60-3.77 (m, 1H), 3.78-3.94(m, 1H), 4.73-4.81 (m, 1H), 6.25 (s, 1H), 8.26 (d, 1H), 8.30 (s, 1H),9.31 (s, 1H). Separation by chiral HPLC provided enantiomers 6a and 6b.

Example 11 Preparation of Compound Nos. 7, 7a and 7b

To a solution of1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (300 mg, 0.847 mmol) in DMF (4 mL) was added pyrimidin-5-amine (201mg, 2.11 mmol), HATU (386 mg, 1.016 mmol) and DIPEA (0.24 mL, 1.4 mmol).The reaction mixture was allowed to stir at RT for 16 h. The reactionmixture was diluted with water (40 mL) and extracted with EtOAc (2×25mL). The organic layer was washed with water (8×30 mL) and dried overanhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave acrude product that was purified by reverse phase HPLC to afford 11 mg of1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamideas free base. ¹H NMR (400 MHz, CD₃OD, formate salt) δ (ppm): 0.58-0.67(m, 2H), 0.80-0.94 (m, 2H), 1.70-1.78 (m, 1H), 2.09-2.21 (m, 4H),2.22-2.42 (m, 2H), 2.78-2.81 (m, 2H), 2.82-2.95 (m, 2H), 3.60-2.70 (m,1H), 3.78-3.88 (m, 1H), 4.78 (dd, 1H), 6.08 (s, 1H), 8.84 (s, 1H), 8.89(s, 2H). Separation by chiral HPLC provided enantiomers 7a and 7b.

Example 12 Preparation of Compound Nos. 8, 8a and 8b

To a solution of 6-fluoropyridin-3-amine (6.05 g, 13 mmol) in dry THF(100 mL) was added 2M solution of isopropylmagnesium chloride in THF (27mL, 54 mmol) dropwise under nitrogen at 0° C. The resultant mixture wasstirred at 0° C. for 20 min. To this solution was added a solution ofmethyl1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(5 g, 13 mmol) in THF (20 mL) dropwise at 0° C. and the reaction mixturewas allowed to stir at RT for 2 h. The reaction was quenched withsaturated ammonium chloride solution (50 mL). The product was extractedwith EtOAc (2×40 mL) and the organic layer was dried over anhydroussodium sulfate. Removal of EtOAc under reduced pressure gave solidresidue which was purified by column chromatography on silica gel using1-2% MeOH-DCM system as eluent followed by chiral purification to afford(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(2.2 g). ¹H NMR (CDCl₃, freebase) δ (ppm): 1.22 (d, 6H), 1.90-2.21 (m,6H), 2.60-2.70 (m, 1H), 2.72 (t, 2H), 2.88 (t, 2H), 2.81-2.96 (m, 1H),3.60-3.80 (m, 2H), 4.77 (d, 2H), 6.40 (s, 1H), 6.74 (s, 1H), 6.82 (d,1H), 7.90 (s, 1H), 8.13 (s, 1H). The other enantiomer was prepared usingthe (R) chiral starting material.

Example 13 Preparation of Compound Nos. 9, 9a and 9b

To a solution of 6-fluoropyridin-3-amine (586 mg, 5.2 mmol) in dry THF(20 mL) was added 2M solution of isopropylmagnesium chloride in THF (2.6mL, 5.2 mmol) dropwise under nitrogen at 0° C. The resultant mixture wasstirred at 0° C. for 20 min. To this solution was added a solution ofmethyl1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxylate(500 mg, 1.31 mmol) in THF (4 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at RT for 3 h. The reaction was quenchedwith saturated ammonium chloride solution (40 mL). The product wasextracted with EtOAc (2×75 mL) and the organic layer was dried overanhydrous sodium sulfate. Removal of EtOAc under reduced pressureafforded an oily residue that was purified by reverse phase HPLC toafford1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide(12 mg). ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 0.58-0.68 (m, 2H),0.82-0.97 (m, 2H), 1.60-1.90 (m, 6H), 2.10-2.24 (m, 3H), 2.30-2.41 (m,1H), 2.77-2.81 (m, 2H), 2.81-2.91 (m, 2H), 4.46 (d, 1H), 5.39 (s, 1H),6.06 (s, 1H), 7.00 (dd, 1H), 8.02-8.12 (m, 1H), 8.27 (s, 1H). Separationby chiral HPLC provided enantiomers 9a and 9b.

Example 14 Preparation of Compound Nos. 10, 10a, 10b, 10c and 10d

To a solution of1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxypyrrolidine-2-carboxylicacid (200 mg, 0.54 mmol) in DMF (3 mL) was added 6-fluoropyridin-3-amine(121 mg, 1.08 mmol), HATU (246 mg, 0.648 mmol) and DIPEA (0.16 mL, 0.864mmol). The reaction mixture was allowed to stir at RT for 16 h. Thereaction mixture was diluted with EtOAc (50 mL), washed with water (4×25mL) and dried over anhydrous sodium sulfate. Removal of EtOAc underreduced pressure gave a crude product that was purified by reverse phaseHPLC to afford(2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide(10 mg). Compound No. 10a: ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm):0.60-0.68 (m, 2H), 0.80-0.92 (m, 2H), 1.71-1.81 (m, 1H), 1.90-2.01 (m,1H), 2.03-2.17 (m, 2H), 2.30-2.41 (m, 2H), 2.65-2.83 (m, 4H), 3.75-3.91(m, 2H), 4.51-4.60 (m, 1H), 6.07 (s, 1H), 6.97 (d, 1H), 7.99 (s, 1H),8.19 (s, 1H). Compound No. 10b: ¹H NMR (400 MHz, CD₃OD, freebase) δ(ppm): 0.60-0.68 (m, 2H), 0.80-0.92 (m, 2H), 1.71-1.81 (m, 1H),1.90-2.01 (m, 1H), 2.03-2.17 (m, 2H), 2.30-2.41 (m, 2H), 2.65-2.83 (m,4H), 3.75-3.91 (m, 2H), 4.51-4.60 (m, 1H), 6.07 (s, 1H), 6.97 (d, 1H),7.99 (s, 1H), 8.19 (s, 1H). Separation by chiral HPLC providedadditional diastereomers 10c and 10d.

Example 15 Preparation of Compound Nos. 11, 11a, 11b, 11c and 11d

To a solution of 6-fluoropyridin-3-amine (292 mg, 2.61 mmol) in dry THF(12 mL) was added 2M solution of isopropylmagnesium chloride in THF (1.3mL, 2.60 mmol) dropwise under nitrogen at 0° C. The resultant mixturewas stirred at 0° C. for 20 min. To this solution was added a solutionof (3S)-methyl1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3-hydroxypyrrolidine-2-carboxylate(250 mg, 0.65 mmol) in THF (2 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at RT for 2 h. The reaction was quenchedwith saturated ammonium chloride solution (50 mL). The product wasextracted with EtOAc (2×40 mL) and the organic layer was dried overanhydrous sodium sulfate. Removal of EtOAc under reduced pressureafforded an oily residue that was purified by reverse phase HPLC toafford(2R,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide(10 mg). Compound No. 11a: ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm):0.60-0.68 (m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H),2.19-2.30 (m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m,2H), 6.28 (brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H).Compound No. 11b: ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 0.60-0.68(m, 2H), 0.82-0.96 (m, 2H), 1.77 (brs, 1H), 2.00-2.18 (m, 3H), 2.19-2.30(m, 1H), 2.70-2.83 (m, 4H), 3.78-3.98 (m, 2H), 4.58-4.77 (m, 2H), 6.28(brs, 1H), 6.98 (d, 1H), 8.02 (brs, 1H), 8.23 (s, 1H). Separation bychiral HPLC provided additional diastereomers 11c and 11d.

Example 16 Preparation of Compound Nos. 12, 12a and 12b

To a solution of1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (300 mg, 0.840 mmol) in DMF (3 mL) was added6-fluoropyridin-3-amine (188 mg, 1.680 mmol), HATU (383 mg, 1.008 mmol)and DIPEA (216 mg, 1.68 mmol). The reaction mixture was allowed to stirat RT for 16 h. The reaction mixture was diluted with water (40 mL) andextracted with EtOAc (2×25 mL). The organic layer was washed with water(8×30 mL) and dried over anhydrous sodium sulfate. Removal of EtOAcunder reduced pressure gave a crude product that was purified by reversephase HPLC to afford a racemic mixture (30 mg). The enantiomers wereseparated by chiral HPLC to afford(R)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(10 mg), and its (S) enantiomer. ¹H NMR (400 MHz, CD₃OD, freebase) δ(ppm): 1.10-1.30 (m, 6H), 2.01-2.18 (m, 4H), 2.20-2.38 (m, 1H),2.39-2.46 (m, 1H), 2.77-2.90 (m, 5H), 3.60-3.78 (m, 1H), 3.87-3.97 (m,1H), 4.67 (dd, 1H), 6.25 (brs, 1H), 7.01 (dd, 1H), 8.02-8.12 (m, 1H),8.31 (s, 1H).

Example 17 Preparation of Compound Nos. 13, 13a and 13b

To a solution of 6-fluoropyridin-3-amine (1.41 g, 12.5 mmol) in THF (30mL) was added 2M solution of isopropylmagnesium chloride in THF (6.2 mL,12.4 mmol) dropwise at 0° C. The resultant mixture was stirred at thesame temperature for 20 min followed by the dropwise addition of asolution of methyl1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate(1.2 g, 3.12 mmol) in THF (10 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h. The progress of reaction was monitored by TLC andLCMS. The reaction mixture was quenched with saturated aqueous NH₄Cl (40mL) and was extracted with EtOAc (3×50 mL). The organic layer was washedwith water (50 mL), dried over anhydrous sodium sulfate and concentratedunder vacuum to obtain a crude product which was purified by columnchromatography on silica (100-200 mesh using 1% MeOH-DCM system aseluent to affordN-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide(750 mg) as racemate. The enantiomers were separated by chiral HPLC toafford(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide (200 mg), and its(S) enantiomer. ¹H NMR (400 MHz, CDCl₃, freebase) δ (ppm): 1.10-1.30 (m,6H), 1.80-2.20 (m, 7H), 2.35-2.46 (m, 2H), 2.58-2.80 (m, 3H), 2.81-2.99(m, 1H), 3.58-3.77 (m, 2H), 4.75 (brs, 1H), 6.20 (s, 1H), 6.83 (dd, 1H),6.95 (s, 1H), 7.91 (s, 1H), 8.18 (s, 1H), 10.80 (brs, 1H).

Example 18 Preparation of Compound Nos. 14, 14a and 14b

To a stirred solution of 6-fluoropyridin-3-amine (2.58 g, 23.01 mmol) inTHF (40 mL) was added a 2M solution of isopropylmagnesium chloride inTHF (11.5 mL, 23 mmol) at 0° C. After 20 min of stirring, to this wasadded a solution of methyl1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate(2.2 g, 5.75 mmol) in THF (10 mL) at 0° C. The reaction mixture wasfurther stirred at RT for 2 h. After completion of reaction it wasquenched with saturated ammonium chloride and the aqueous layer wasextracted with EtOAc (3×50 mL). The combined organic layer was treatedwith brine, dried over Na₂SO₄ and evaporated under reduced pressure toobtain a crude product, which was purified by column chromatography on100-200 mesh silica gel using MeOH-DCM (1:10) as eluent to obtain asracemate (0.6 g, 23% yield). The enantiomers were separated by chiralHPLC to afford(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide(130 mg), and its (S) enantiomer. ¹H NMR (400 MHz, CDCl₃, freebase) δ(ppm): 0.60-0.77 (m, 2H), 0.85-0.98 (m, 2H), 1.77-1.90 (m, 6H),1.91-2.20 (m, 3H), 2.38-2.43 (m, 2H), 2.60-2.80 (m, 3H), 3.59-3.78 (m,2H), 4.71 (d, 1H), 6.17 (s, 1H), 6.80-6.83 (m, 1H), 6.91 (s, 1H), 7.95(s, 1H), 8.20 (brs, 1H), 10.90 (brs, 1H).

Example 19 Preparation of Compound Nos. 15, 15a and 15b

To a stirred solution of 6-fluoropyridin-3-amine (1.32 g, 11.77 mmol) inTHF (30 mL) was added a 2M solution of isopropylmagnesium chloride inTHF (5.9 mL, 11.8 mmol) at 0° C. After 20 min of stirring, to this wasadded a solution of methyl1-(4-(3-cyclopentyl-1H-pyrazol-5-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate(1.2 g, 2.92 mmol) in THF (10 mL) at 0° C. The reaction mixture wasfurther stirred at RT for 2 h. After completion of reaction it wasquenched with saturated ammonium chloride and the aqueous layer wasextracted with EtOAc (3×50 mL). The combined organic layer was treatedwith brine, dried over Na₂SO₄ and evaporated under reduced pressure toobtain a crude product, which was purified by column chromatography on100-200 mesh silica gel using MeOH-DCM (1:10) as eluent to obtainracemic mixture (842 mg, 59% yield). Chiral separation of 200 mg ofenantiomeric mixture afforded(R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide(50 mg), and its (S) enantiomer. ¹H NMR (400 MHz, CDCl₃, freebase) δ(ppm): 1.42-1.79 (m, 6H), 1.80-2.20 (m, 10H), 2.38-2.43 (m, 2H),2.60-2.78 (m, 3H), 2.96-3.04 (m, 1H), 3.58-3.70 (m, 2H), 4.72 (d, 1H),6.42 (s, 1H), 6.78-6.82 (m, 1H), 6.97 (s, 1H), 7.85 (s, 1H), 8.16 (s,1H), 10.90 (brs, 1H).

Example 20 Preparation of Compound Nos. 16, 16a and 16b

To a stirred solution of 6-fluoropyridin-3-amine (2.4 g, 21.4 mmol) inTHF (25 mL) was added a 2M solution of isopropylmagnesium chloride inTHF (10.4 mL, 20.8 mmol) at 0° C. After 20 min of stirring, to this wasadded a solution of methyl1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxylate(2 g, 5.2 mmol) in THF (10 mL) at 0° C. The reaction mixture was furtherstirred at RT for 2 h. After completion of reaction it was quenched withsaturated ammonium chloride and the aqueous layer was extracted withEtOAc (3×50 mL). The combined organic layer was treated with brine,dried over Na₂SO₄ and evaporated under reduced pressure to obtain acrude product which was purified by reverse phase HPLC to afford aracemic mixture (100 mg). The enantiomers were separated by chiral HPLCto afford(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide(40 mg), and its (S) enantiomer. ¹H NMR (400 MHz, CD₃OD, freebase) δ(ppm): 1.18-1.25 (m, 6H), 1.27-1.38 (m, 1H), 1.65-1.82 (m, 3H),2.20-2.34 (m, 2H), 2.41-2.250 (m, 1H), 2.79-2.85 (m, 2H), 2.92-3.00 (m,1H), 3.00-3.08 (m, 2H), 3.40-3.51 (m, 2H), 4.09-4.17 (m, 1H), 5.38 (s,1H), 6.21 (s, 1H), 7.00-7.08 (m, 1H), 8.10-8.17 (m, 1H), 8.30 (s, 1H).

Example 21 Preparation of Compound Nos. 17, 17a and 17b

To a stirred solution of 6-fluoropyridin-3-amine (2.3 g, 20.5 mmol) inTHF (35 mL) was added a 2M solution of isopropylmagnesium chloride inTHF (10.3 mL, 20.6 mmol) at 0° C. After 20 min of stirring, to this wasadded a solution of methyl1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxylate(2.1 g, 5.12 mmol) in THF (10 mL) at 0° C. The reaction mixture wasfurther stirred at RT for 2 h. After completion of reaction it wasquenched with saturated ammonium chloride and the aqueous layer wasextracted with EtOAc (3×50 mL). The combined organic layer was treatedwith brine, dried over Na₂SO₄ and evaporated under reduced pressure toobtain a crude product which was purified by reverse phase HPLC toafford a racemic mixture (120 mg). The enantiomers were separated bychiral HPLC to afford(R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide(35 mg), and its (S) enantiomer. ¹H NMR (400 MHz, CD₃OD, freebase) δ(ppm): 1.51-1.81 (m, 10H), 1.95-2.05 (m, 2H), 2.06-2.17 (m, 2H),2.50-2.32 (m, 1H), 2.25-2.39 (m, 2H), 2.70-2.82 (m, 4H), 2.98-3.05 (m,1H), 4.61 (brs, 1H), 5.45 (s, 1H), 6.26 (s, 1H), 6.99 (d, 1H), 8.00-8.05(m 1H), 8.25 (s, 1H).

Example 22 Preparation of Compound Nos. 18, 18a and 18b

To a solution of (R)-methyl1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(500 mg, 1.351 mmol) in THF (10 mL) was added 28% aqueous ammonia (20mL) and reaction mixture was allowed to stir at 60° C. for 24 h. Theprogress of reaction was monitored by LCMS. The reaction mixture wasdiluted with water (100 mL) and extracted with EtOAc (2×100 mL). Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under vacuum to obtain a crude product which was purifiedby reverse phase HPLC to afford(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(80 mg). ¹H NMR (400 MHz, DMSO-d₆, freebase) δ (ppm): 1.22 (d, 6H),1.81-2.01 (m, 6H), 2.02-2.18 (m, 1H), 2.59-2.70 (m, 4H), 2.86-2.92 (m,1H), 3.48 (brs, 1H), 3.67 (brs, 1H), 4.35 (d, 1H), 6.43 (brs, 1H), 6.85(s, 1H), 7.18 (s, 1H), 8.78 (brs, 1H). The other enantiomer was preparedusing the (R) chiral starting material.

Example 23 Preparation of Compound Nos. 19, 19a and 19b

To a solution of1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (300 mg, 0.842 mmol) in DMF (5 mL) was added methylaminehydrochloride (284 mg, 4.207 mmol), HATU (320 mg, 0.842 mmol),diisopropylethylamine (163 mg, 1.263 mmol). The reaction mixture wasstirred at RT for 16 h. The progress of reaction was monitored by LCMS.The reaction mixture was diluted with water (20 mL) and extracted withEtOAc (3×30 mL). The organic layer was washed with water (8×40 mL) anddried over anhydrous sodium sulfate. Removal of solvent under vacuumgave a crude product which was purified by reverse HPLC to obtain pure1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide(20 mg) as racemate. The enantiomers were separated by chiral HPLC toafford(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide(5 mg). ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 1.30 (d, 6H),1.95-2.25 (m, 6H), 2.68 (s, 3H), 2.74 (t, 2H), 2.78 (t, 2H), 2.93-3.03(m, 1H), 3.59 (brs, 1H), 3.80 (brs, 1H), 4.54 (d, 1H), 6.40 (brs, 1H).The other enantiomer was made using the chiral (R) starting material.

Example 24 Preparation of Compound Nos. 20, 20a and 20b

To a solution of1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (300 mg, 0.842 mmol) in DMF (5 mL) was added dimethyl aminehydrochloride (343 mg, 4.213 mmol), HATU (320 mg, 0.842 mmol),diisopropylethylamine (163 mg, 1.263 mmol) and the reaction mixture wasstirred at RT for 16 h. The progress of reaction was monitored by LCMS.The reaction mixture was diluted with water (20 mL) and extracted withEtOAc (3×30 mL). The organic layer was washed with water (8×40 mL) anddried over anhydrous sodium sulfate. Removal of solvent under reducedpressure gave a crude product which was purified by reverse phase HPLCfollowed by chiral HPLC to afford(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N,N-dimethylpyrrolidine-2-carboxamide,and its (S) enantiomer. ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 1.28(d, 6H), 1.90-2.18 (m, 5H), 2.30-2.42 (m, 1H), 2.62-3.08 (m, 4H), 2.76(s, 3H), 2.82-2.30 (m, 1H), 2.98 (s, 3H), 3.61-3.91 (m, 2H), 5.01 (d,1H), 6.00 (brs, 1H).

Example 25 Preparation of Compound Nos. 21, 21a and 21b

Step-1: Synthesis of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate

To a suspension of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (15 g,114.5 mmol) in MeOH (150 mL) was added SOCl₂ (17 mL, 229 mmol) dropwiseat 0° C. The resultant mixture was allowed to stir at RT overnight. Thereaction mixture was concentrated under vacuum, azeotroped with tolueneand dried to afford (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate asthe HCl salt (20.5 g).

Step-2: Synthesis of(2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-hydroxy pyrrolidine

To a suspension of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylatehydrochloride (20.5 g, 113.25 mmol) in DCM was added triethylamine (31.4mL, 226.5 mmol), DMAP (690 mg, 5.66 mmol) and di-tert-butyl dicarbonate(29.6 g, 135.9 mmol) at 0° C. The reaction mixture was allowed to stirat RT for 3 h. the reaction mixture was washed with water (3×150 mL)followed by saturated NaHCO₃ (150 mL) and brine (150 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum to afford(2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-hydroxy pyrrolidine asoil (27 g).

Step-3: Synthesis of(2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-methoxy pyrrolidine

To a solution of(2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-hydroxy pyrrolidine (10g, 40.81 mmol) in DMF (60 mL) at 0° C. was added NaH (2.9 g, 122.4 mmol)and the resultant mixture was allowed to stir at the same temperaturefor 30 min. To this mixture was added MeI (5.08 mL, 81.63 mmol) dropwiseat 0° C. and the reaction mixture was allowed to stir at RT for 2 h. Thereaction mixture was poured onto ice-cold water (200 mL) and extractedwith EtOAc (250 mL). The organic layer was washed with water (8×100 mL)and dried over anhydrous sodium sulfate. Removal of solvent underreduced pressure afforded(2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-methoxy pyrrolidine (9g) which was used for the next step without further purification.

Step-4: Synthesis of (2S,4R)-methyl 4-methoxypyrrolidine-2-carboxylatehydrochloride

A solution of (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-methoxypyrrolidine (9 g, 34.74 mmol) in 4 M HCl-dioxane (13 mL) was stirred atRT overnight. The reaction mixture was concentrated to dryness, washedwith hexane followed by ether and dried under vacuum to afford(2S,4R)-methyl 4-methoxypyrrolidine-2-carboxylate hydrochloride (6 g).

Step-5: Synthesis of(4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylicacid

To a solution of2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(5 g, 13.5 mmol) in NMP (20 mL) was added DIPEA (3.6 mL) and 5 N NaOH(4.05 mL) and the resultant mixture was allowed to stir at 135° C. for20 h. The reaction mixture was diluted with water (100 mL) and extractedwith EtOAc (6×80 mL). The aqueous layer was acidified with 1N HClsolution up to pH 4 and extracted with EtOAc (3×60 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum to afford(4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylicacid (4.9 g).

Step-6: Synthesis of (4R)-methyl1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate

To a solution of(4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylicacid (3.5 g, 9.11 mmol) in MeOH (20 mL) was added HOBt.H₂O (2.27 g, 4.56mmol), N-methylmorpholine (2 mL, 18.22 mmol) and EDCI.HCl (2.44 g, 12.75mmol). The reaction mixture was allowed to stir at RT for 1 h. MeOH wasremoved under reduced pressure and the residue was dissolved in EtOAc(200 mL). The solution was washed with water (10×100 mL) followed bybrine (100 mL) and dried over anhydrous sodium sulfate. Removal of EtOAcunder reduced pressure afforded (4R)-methyl1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate(3 g).

Step-7: Synthesis of(4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide

To a solution of 6-fluoropyridin-3-amine (1.2 g, 11.30 mmol) in dry THF(20 mL) was added 2M solution of isopropylmagnesium chloride in THF (9.4mL, 18.8 mmol) dropwise under nitrogen at 0° C. The resultant mixturewas stirred at 0° C. for 20 min. To this solution was added a solutionof (4R)-methyl1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxylate(3 g, 7.53 mmol) in THF (10 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at RT overnight. The reaction was quenchedwith saturated ammonium chloride solution (50 mL). The product wasextracted with EtOAc (2×100 mL) and the organic layer was dried overanhydrous sodium sulfate. Removal of EtOAc under reduced pressureafforded a diastereomeric mixture of Compound 21. The diastereomers wereseparated by reverse phase followed by chiral HPLC to afford(2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide(Compound No. 21a, 208 mg) and(2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide(Compound No. 21b, 193 mg). Compound No. 21a: ¹H NMR (400 MHz, CD₃OD,freebase) δ (ppm): 0.60-0.78 (m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m,1H), 2.08-2.20 (m, 2H), 2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s,3H), 2.70-2.81 (m, 1H), 3.90-4.02 (m, 1H), 4.15-4.21 (m, 1H), 4.72-4.78(m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H), 8.00 (brs, 1H), 8.28 (brs, 1H).Compound No. 21b: ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 0.60-0.78(m, 2H), 0.82-0.98 (m, 2H), 1.78-1.82 (m, 1H), 2.08-2.20 (m, 2H),2.38-2.62 (m, 2H), 2.78-2.91 (m, 4H), 3.40 (s, 3H), 3.80-4.01 (m, 2H),4.15-4.21 (m, 1H), 4.72-4.78 (m, 1H), 6.21 (brs, 1H), 7.00 (dd, 1H),8.00 (brs, 1H), 8.28 (brs, 1H).

Example 26 Preparation of Compound Nos. 22, 22a, 22b, 22c and 22d

To a stirred solution of (3S)-tert-butyl3-(1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyrrolidine-1-carboxylate(350 mg, 0.667 mmol) in DCM (3.5 mL) was added TFA (0.15 ml, 2.003 mmol)dropwise under nitrogen atmosphere at 0° C. The resultant mixture wasstirred at RT for 16 h. The reaction mixture was concentrated underreduced pressure. The crude obtained was purified by reverse phase HPLC.The stereoisomers obtained were separated by chiral HPLC to afford 21 mgof(R)-1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide.¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.30 (d, 6H), 1.94-2.15 (m, 6H),2.60-2.77 (m, 4H), 2.79-3.10 (m, 6H), 3.58-3.66 (m, 1H), 3.70-3.80 (m,1H), 4.05-4.13 (m, 1H), 4.58 (dd, 1H), 6.38 (s, 1H), 6.79 (s, 1H). Theother diastereomers were prepared using appropriate chiral startingmaterials.

Example 27 Preparation of Compound Nos. 23 to 49, 51 to 54, 56 to 59, 61to 62, 64 to 67, 75 to 77, 80 to 83, 85 to 94 and Stereoisomers

Compound Nos. 23 to 49, 51 to 54, 56 to 59, 61 to 62, 64 to 67, 75 to77, 80 to 83, 85 to 94, and their individual stereoisomers, can beprepared in a similar fashion according to the General Method, Examples,and publications described herein, and from established syntheticprocedures familiar to those skilled in the art.

Example 28 Preparation of Compound Nos. 50, 50a and 50b

To a stirred solution of 5-amino-2-fluoropyridine (79 mg, 0.703 mmol) indry THF (2 mL) was added isopropyl magnesium chloride 2M in THF (0.43mL, 0.86 mmol) dropwise under nitrogen atmosphere at 0° C. The resultantmixture was stirred at 0° C. for 30 min. To this was added a solution of(S)-methyl1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(70 mg, 0.175 mmol) in THF (2 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at RT for 2 h. The reaction mixture wascooled to 0° C. and quenched by saturated ammonium chloride solution (10mL). The reaction mixture was diluted with water (10 mL) and extractedwith EtOAc (2×20 mL). The organic layer was washed with brine (20 mL)and dried over anhydrous sodium sulfate. Removal of EtOAc under vacuumgave a crude oil which was purified by reverse phase HPLC to afford 15mg of(S)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide.¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 1.15-1.25 (m, 6H), 1.20 (s,6H), 2.02-2.18 (m, 2H), 2.22-2.3.8 (m, 2H), 2.58 (s, 2H), 2.62 (s, 2H),2.79-2.90 (m, 1H), 3.60-3.70 (m, 1H), 3.78-3.87 (m, 1H), 4.77 (dd, 1H),6.25 (brs, 1H), 6.99 (dd, 1H), 7.97 (brs, 1H), 8.20 (s, 1H). The otherenantiomer was obtained using the chiral (R) starting material.

Example 29 Preparation of Compound Nos. 55, 55a and 55b

To a solution of 6-fluoro-N-methyl-pyridin-3-amine (1.05 g, 8.34 mmol)in THF (15 mL) was added isopropylmagnesium chloride (2M in THF) (4.15mL, 8.34 mmol) dropwise at 0° C. The reaction mixture was stirred at thesame temperature for 30 min. followed by the dropwise addition ofsolution of ethyl(2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate(0.8 g, 2.083 mmol) in THF (5 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h. The progress of reaction was monitored by LCMS.The reaction mixture was quenched with saturated solution of ammoniumchloride (30 mL) and extracted with EtOAc (2×30 mL). The organic layerwas washed with water (40 mL) followed by brine (20 mL), dried overanhydrous sodium sulfate and concentrated under vacuum to obtain crudewhich was purified by reverse phase HPLC to afford(2S)—N-(6-fluoro-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-N-methylpyrrolidine-2-carboxamide(190 mg) as solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.19-1.30 (m, 6H),1.80-2.30 (m, 6H), 2.58-2.68 (m, 2H), 2.70-2.88 (m, 2H), 2.91-3.00 (m,1H), 3.28 (s, 3H), 3.61-3.78 (m, 1H), 3.79-3.90 (m, 1H), 4.40 (brs, 1H),6.18 (s, 1H), 6.66 (s, 1H), 7.00 (brs, 1H), 8.01 (brs, 1H), 8.20 (s,1H). The other enantiomer was obtained by using the chiral (R) startingmaterial.

Example 30 Preparation of Compound Nos. 60, 60a and 60b

To a solution of(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(200 mg, 0.44 mmol) and urea-hydrogen peroxide (125 mg, 1.33 mmol) inDCM (10 mL) at 0° C. was added trifluoroacetic anhydride (280 mg, 1.33mmol). The resulting mixture was allowed to stir at RT overnight. Thereaction mixture was concentrated under reduced pressure to afford anoily residue that was diluted with saturated sodium bicarbonate solution(10 mL), and the product was extracted with EtOAc (2×25 mL). Thecombined organic layer was dried over anhydrous sodium sulfate. Removalof EtOAc under reduced pressure gave an oily residue that was purifiedby reverse phase HPLC to afford 10 mg of(S)-2-fluoro-5-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine1-oxide. ¹HNMR (400 MHz, CD₃OD) δ (ppm): 1.20 (d, 6H), 2.02-2.18 (m,4H), 2.21-2.36 (m, 2H), 2.75-2.93 (m, 5H), 3.60-3.70 (m, 1H), 3.77-3.84(m, 1H), 4.77 (dd, 1H), 6.21 (s, 1H), 7.36-7.41 (m, 1H), 7.50 (s, 1H),8.81-8.89 (m, 1H). The other enantiomer was obtained using chiral (R)starting material.

Example 31 Preparation of Compound Nos. 63, 63a and 63b

To a solution ofN-(6-fluoro-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxamide(500 mg, 1.111 mmol) in THF (10 mL) was added HCl (1 mL) and reactionmixture was stirred at 60° C. for 16 h. The progress of reaction wasmonitored by LCMS. The reaction mixture was concentrated under vacuum toobtain crude product which was purified by reverse HPLC to affordN-(6-hydroxy-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxamide(249 mg). ¹H NMR (400 MHz, CD₃OD) δ (ppm): 1.17-1.30 (m, 6H), 2.17-2.37(m, 4H), 2.38-2.50 (m, 1H), 2.79-2.95 (m, 3H), 3.00-3.10 (m, 2H),3.22-3.38 (m, 2H), 3.58-3.70 (m, 1H), 3.80 (brs, 1H), 4.81 (dd, 1H),6.22 (s, 1H), 6.68 (d, 1H), 7.60 (d, 1H), 7.98 (s, 1H). Separation bychiral HPLC provides enantiomers 63a and 63b.

Example 32 Preparation of Compound Nos. 68, 68a and 68b

To a solution of thiazol-2-amine (1.08 g, 10.8 mmol) in THF (12 mL) wasadded isopropyl magnesium chloride (5.4 mL, 10.8 mmol) dropwise at 0° C.The reaction mixture was stirred at the same temperature for 20 min.,followed by dropwise addition of solution of methyl(2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate(1 g, 2.702 mmol) in THF (5 mL). The reaction mixture was stirred at RTfor 2 h. The progress of reaction was monitored by LCMS. The reactionmixture was quenched with a saturated solution of ammonium chloride (200mL) and extracted with EtOAc (2×200 mL). The organic layer was washedwith water (2×200 mL) followed by brine (200 mL) and dried overanhydrous sodium sulfate and concentrated under vacuum to obtain a crudeproduct, which was recrystallized in diethyl ether (50 mL) to afford(2S)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-N-thiazol-2-yl-pyrrolidine-2-carboxamide(600 mg). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 1.30 (d, 6H), 2.00-2.22 (m,5H), 2.50-2.70 (m, 3H), 2.80-3.05 (m, 3H), 3.61-3.80 (m, 2H), 4.85 (d,1H), 6.28 (brs, 1H), 6.93 (d, 1H), 6.99 (brs, 1H), 7.40 (d, 1H). Theother enantiomer is prepared using chiral (R) starting material.

Example 33 Preparation of Compound Nos. 69, 69a and 69b

To a solution of 6-fluoropyridin-3-amine (247 mg, 2.6 mmol) in dry THF(6 mL) was added a 2M solution of isopropylmagnesium chloride (1.3 mL,2.6 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixturewas stirred at 0° C. for 20 minutes. To this solution was added asolution of (S)-ethyl1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(200 mg, 0.52 mmol) in THF (2 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at room temperature for 2 h. The reactionwas quenched with saturated ammonium chloride solution (10 mL). Theproduct was extracted with ethyl acetate (3×50 mL). The combined organiclayer was washed with water (2×100 mL) and dried over anhydrous sodiumsulfate. Removal of ethyl acetate under reduced pressure gave solidresidue which was purified by reverse phase HPLC to afford 119 mg of(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamideas TFA salt. ¹H NMR (400 MHz, CD₃OD, TFA) δ (ppm): 1.00-1.22 (m, 6H),2.10-2.39 (m, 5H), 2.40-2.48 (m, 1H), 2.79-2.91 (m, 3H), 2.97-3.10 (m,2H), 3.60-3.86 (m, 2H), 4.80-4.91 (m, 1H), 6.16 (s, 1H), 8.10 (d, 1H),8.58 (d, 1H), 8.87. The other enantiomer is prepared using chiral (R)starting material.

Example 34 Preparation of Compound Nos. 70, 70a, 70b, 70c and 70d

To a solution of 6-fluoropyridin-3-amine (4.64 mg, 4.14 mmol) in dry THF(5 mL) was added 2 M solution of isopropylmagnesium chloride (1.98 mL,3.96 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixturewas stirred at 0° C. for 20 min. To this solution was added a solutionof (2S,4R)-methyl4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(400 mg, 1.04 mmol) in THF (2 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at 25° C. for 4 h. The reaction was quenchedwith saturated ammonium chloride solution (10 mL) and diluted with water(25 mL). The product was extracted with EtOAc (2×50 mL). The combinedorganic layer was washed with water (2×100 mL) followed by brine (100mL) and dried over anhydrous sodium sulfate. Removal of EtOAc underreduced pressure gave an oily residue which was purified by reversephase HPLC to afford 66 mg of(2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide.¹H NMR (400 MHz, CDCl₃, freebase) δ (ppm): 0.99-1.30 (m, 6H), 2.10-2.30(m, 4H), 2.65-2.74 (m, 2H), 2.78-2.98 (m, 4H), 3.78-3.05 (m, 1H),3.91-3.99 (m, 1H), 4.70-4.78 (m, 1H), 4.92-4.98 (m, 1H), 6.34 (s, 1H),6.77 (s, 1H), 6.82 (dd, 1H), 7.93 (s, 1H), 8.08-8.18 (m, 1H). The otherdiasteromers are prepared using appropriate chiral starting materials.

Example 35 Preparation of Compound Nos. 71, 71a, 71b, 71c and 71d

To a solution of 6-fluoropyridin-3-amine (415 mg, 4.15 mmol) in dry THF(5 mL) was added a 2M solution of isopropylmagnesium chloride (2.08 mL,4.16 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixturewas stirred at 0° C. for 20 min. To this solution was added a solutionof (2S,4R)-methyl4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(400 mg, 1.04 mmol) in THF (2 mL) dropwise at 0° C. and the reactionmixture was allowed to stir at 25° C. for 4 h. The reaction was quenchedwith saturated ammonium chloride solution (10 mL) and diluted with water(25 mL). The product was extracted with EtOAc (2×75 mL). The combinedorganic layer was washed with water (2×100 mL) followed by brine (100mL) and dried over anhydrous sodium sulfate. Removal of EtOAc underreduced pressure gave an oily residue which was purified by reversephase HPLC to afford 95 mg of(2S,4R)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide.¹H NMR (400 MHz, CDCl₃, freebase) δ (ppm): 1.20-1.39 (m, 6H), 2.05-2.18(m, 2H), 2.19-2.27 (m, 1H), 2.58-2.78 (m, 3H), 2.79-3.06 (m, 3H),3.79-3.06 (m 1H), 3.91-4.00 (m, 1H), 4.71-4.78 (m, 1H), 4.98-5.05 (m,1H), 6.22 (s, 1H), 6.92 (d, 1H), 7.40 (d, 1H). The other diasteromersare prepared using appropriate chiral starting materials.

Example 36 Preparation of Compound Nos. 72, 72a and 72b

To a solution of(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(250 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was added aqueous ammonia (5mL) and the reaction mixture was allowed to reflux in steel bomb at 130°C. for 18 h. The reaction mixture was concentrated under vacuum toobtain an oily crude product which was purified by reverse phase HPLC toafford 8 mg of(S)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide.¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 1.20 (d, 6H), 2.00-2.20 (m,4H), 2.75-2.95 (m, 5H), 3.50-3.90 (m, 4H), 4.90-4.98 (m, 1H), 6.40 (s,1H), 6.50 (d, 1H), 7.40 (s, 1H), 7.90 (s, 1H). The other enantiomer isprepared using the chiral (R) starting material.

Example 37 Preparation of Compound Nos. 73, 73a and 73b

A mixture of1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (400 mg, 1.12 mmol), piperidine (143 mg, 1.68 mmol), HATU (512 g,1.34 mmol) and DIPEA (230 mg, 1.79 mmol) in DMF (4 mL) was allowed tostir at RT overnight. The reaction mixture was diluted with water (50mL) and extracted with EtOAc (2×50 mL). The combined organic layer waswashed with water (8×25 mL) and dried over anhydrous sodium sulfate.Removal of EtOAc gave an oily residue which was purified by reversephase HPLC followed by chiral HPLC to afford 10 mg of(R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(piperidin-1-yl)methanone,and its enantiomer. ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 1.30 (d,6H), 1.40-1.90 (m, 6H), 1.92-2.12 (m, 5H), 2.30-2.42 (m, 1H), 2.65-2.81(m, 4H), 2.90-3.01 (m, 1H), 3.40-3.90 (m, 6H), 5.00-5.08 (m, 1H), 6.00(brs, 1H).

Example 38 Preparation of Compound Nos. 74, 74a and 74b

A mixture of1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (1 g, 2.8 mmol), morpholine (0.366 g, 4.2 mmol), HATU (1.28 g, 3mmol) and DIPEA (0.58 g, 4 mmol) in DMF (5 mL) was allowed to stir at RTovernight. The reaction mixture was diluted with water (50 mL) andextracted with EtOAc (2×50 mL). The combined organic layer was washedwith water (8×25 mL) and dried over anhydrous sodium sulfate. Removal ofEtOAc gave an oily residue which was purified by reverse phase HPLCfollowed by chiral HPLC to afford 15 mg of(R)-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidin-2-yl)(morpholino)methanone,and its enantiomer. ¹H NMR (400 MHz, CD₃OD, freebase) δ (ppm): 1.29 (d,6H), 1.92-2.15 (m, 5H), 2.30-2.42 (m, 1H), 2.67-2.81 (m, 4H), 2.90-3.04(m, 1H), 3.41-3.90 (m, 10H), 4.98-5.08 (m, 1H), 5.85 (brs, 1H).

Example 39 Preparation of Compound Nos. 78, 78a and 78b

A suspension of(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(200 mg, 0.44 mmol) and sodium thiomethoxide (100 mg, 1.42 mmol) inethanol (2 mL) was heated at 100° C. in a microwave for 1 h. The solventwas removed under reduced pressure and the residue was diluted withEtOAc (50 mL). The solution was washed with saturated sodium bicarbonatesolution (20 mL) followed by brine (20 mL), and dried over anhydroussodium sulfate. Removal of EtOAc under reduced pressure gave an oilyresidue that was purified by reverse phase HPLC followed by chiral HPLCto afford 10 mg of(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide.¹HNMR (400 MHz, CDCl₃) δ (ppm): 1.18-1.32 (m, 6H), 1.90-2.20 (m, 5H),2.51 (s, 3H), 2.60-2.77 (m, 3H), 2.84-2.98 (m, 3H), 3.60-3.79 (m, 2H),4.78 (d, 1H), 6.40 (s, 1H), 6.70 (s, 1H), 7.08 (d, 1H), 7.98 (brs, 1H),8.20 (s, 1H). The other enantiomer is prepared using the (S) startingmaterial.

Example 40 Preparation of Compound Nos. 79, 79a and 79b

A suspension of(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(200 mg, 0.44 mmol) and sodium ethoxide (100 mg, 1.42 mmol) in ethanol(2 mL) was heated at 100° C. in a microwave for 1 h. The solvent wasremoved under reduced pressure and the residue was diluted with EtOAc(50 mL). The solution was washed with saturated sodium bicarbonatesolution (20 mL) followed by brine (20 mL) and dried over anhydroussodium sulfate. Removal of EtOAc under reduced pressure gave an oilyresidue that was purified by reverse phase HPLC followed by chiral HPLCto afford 4 mg of(R)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide.¹HNMR (400 MHz, CDCl₃) δ (ppm): 1.18-1.32 (m, 6H), 1.38 (t, 3H),1.90-2.20 (m, 5H), 2.60-2.77 (m, 3H), 2.84-2.98 (m, 3H), 3.60-3.79 (m,2H), 4.28 (q, 2H), 4.78 (d, 1H), 6.40 (s, 1H), 6.62 (d, 1H), 6.70 (s,1H), 7.85 (brs, 1H), 7.79 (s, 1H). The other enantiomer is preparedusing the (S) starting material.

Example 41 Preparation of Compound Nos. 84, 84a and 84b

To a stirred solution of 6-fluoropyridin-3-amine (1 g, 8.916 mmol) indry THF (10 mL) was added isopropyl magnesium chloride 2M in THF (5.2mL, 10.40 mmol) dropwise under nitrogen atmosphere at 0° C. Theresultant mixture was stirred at 0° C. for 30 min. To this was added asolution of methyl(2S)-1-[4-[(3-isopropyl-1H-pyrazol-5-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxylate(1.1 g, 2.972 mmol) in THF (10 mL) dropwise at 0° C. The mixture wasstirred at RT for 2 h. The reaction mixture was cooled to 0° C., andquenched with saturated ammonium chloride solution (50 mL). The productwas extracted with EtOAc (2×50 mL). The organic layer was washed withbrine (50 mL) and dried over anhydrous sodium sulfate. Removal ofsolvent under reduced pressure gave a crude oily residue that wastriturated with ether (3×25 mL) to afford 600 mg of solid product. 50 mgof product was purified by reverse phase HPLC to afford 30 mg of(2S)—N-(2-fluoro-3-pyridyl)-1-[4-[(3-isopropyl-1H-pyrazol-5-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxamide.¹HNMR (400 MHz, CDCl₃) δ (ppm): 1.28 (d, 6H), 1.90-2.00 (m, 1H),2.03-2.21 (m, 4H), 2.62-2.78 (m, 3H), 2.80-3.10 (m, 3H), 3.60-3.80 (m,2H), 4.83 (d, 1H), 6.37 (s, 1H), 6.72 (s, 1H), 7.09-7.18 (m, 1H),7.78-7.82 (m, 1H), 8.77-8.33 (m, 1H). The other enantiomer is preparedusing the (R) chiral starting material.

Example 42 Preparation of Compound Nos. 95, 95a and 95b

To a suspension of(S)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide(25 mg, 0.053 mmol) in ethanol (1 mL) was added Cs₂CO₃ (26 mg, 0.080mmol) and the reaction mixture was allowed to stir at 80° C. for 12 h.The reaction mixture was concentrated, diluted with water (20 mL) andextracted with EtOAc (2×20 mL). The combined organic layer was driedover anhydrous sodium sulfate. Removal of EtOAc under reduced pressuregave an oily residue that was purified by reverse phase HPLC to afford 8mg of(S)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamideas the TFA salt. ¹HNMR (400 MHz, CD₃OD) δ (ppm): 1.00-1.17 (m, 6H), 1.27(t, 3H), 2.08-2.30 (m, 4H), 2.36-2.42 (m, 2H), 2.70-2.90 (m, 3H),2.92-3.03 (m, 2H), 3.60-3.70 (m, 1H), 3.78-3.88 (m, 1H), 4.37 (q, 2H),4.85-4.95 (m, 1H), 6.24 (s, 1H), 6.82-6.92 (m, 1H), 7.78-7.93 (m, 1H),8.10-8.18 (m, 1H). The other enantiomer is prepared using the (R) chiralstarting material.

Example 43 Preparation of Compound Nos. 96, 96a and 96b

To a solution of 6-fluoro-N-methylpyridin-3-amine (272 mg, 2.16 mmol) inTHF (70 mL) was added isopropyl magnesium chloride solution 2M in THF(1.08 mL, 2.16 mmol) dropwise at 0° C. The mixture was allowed to stirat 0° C. for 20 min. Then, a solution of (R)-methyl1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate(200 mg, 0.54 mmol) in THF (3 mL) was added and the reaction mixture wasallowed to stir at RT for 2 h. The reaction was quenched with saturatedammonium chloride solution (50 mL) and the mixture was extracted withEtOAc (3×50 mL). The combined organic layer was washed with brine anddried over anhydrous sodium sulfate. Removal of EtOAc under reducedpressure gave an oily residue that was purified by reverse phase HPLC toafford 17 mg of(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide.¹HNMR (400 MHz, CDCl₃) δ (ppm): 1.20-1.35 (m, 6H), 1.79-2.25 (m, 6H),2.57-2.68 (m, 2H), 2.79-2.82 (m, 2H), 2.91-3.01 (m, 1H), 3.30 (s, 3H),3.59-3.80 (m, 2H), 4.35-4.45 (m, 1H), 6.16 (s, 1H), 6.90-7.05 (m, 2H),8.01 (brs, 1H), 8.40 (brs, 1H). The other enantiomer is prepared usingthe (S) chiral starting material.

Example B1 Western Blot Analysis

Inhibition of Akt phosphorylation induced by IGF-1R was studied bywestern blot analysis. Human colon carcinoma HT-29 cells were seeded ata density of 8×10⁴ cells/well in a 24-well plate and grown in DME/F12media containing 10% FBS for 24 h. The cells were then depleted of serumby incubation in DME/F12 media lacking FBS for 24 h. Next, cells wereincubated for 2 h with compounds of the invention at concentrations of0.1, 1, 10, or 100 ng/mL, and control cells were treated with DMSO(vehicle) or 10 ng/mL IGF-1. Cells in all treatment conditions were thentreated with 10 ng/mL of IGF-1 for 10 min, followed by removal of mediaand addition of 200 μL of lysis buffer (Cell Signaling cat.#9803). Lysedcells were centrifuged at 13,000 rpm for 15 min and the proteinconcentration soluble fraction (supernatant) of each sample wasdetermined using a BCA protein assay (Pierce). Proteins were separatedby gel electrophoresis (10% SDS-PAGE, 10 μg protein/well, 100 h),followed by transfer of the proteins to a PVDF membrane (Bio-Radcat.#162-0177) at 10 V overnight. The membrane was blocked with 5%non-fat dry milk in 1×TBS buffer for 1 h, and then incubated with α-pAKTantibody (1:1000, Cell Signaling cat. #9271) for 3 h. The membrane waswashed 3 times with 1×TBS containing 0.01% Tween-20 (10 min/wash), andincubated with α-rabbit secondary antibody (1:10,000, Rocklandcat.#611-1322) for 1 h. The membrane was again washed 3 times with 1×TBScontaining 0.01% Tween-20 (10 min/wash) and developed usingchemiluminescence (Pierce ECL Western Blotting kit cat.#32106).

Western blot quantification of the protein bands was carried out usingImageJ software (v. 1.46), with quantification of actin used as acontrol whose levels are not affected by the treatments. OSI-906(3-[8-Amino-1-(2-phenyl-7-quinolyl)imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol)and BMS-754807((S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide)were used as controls to detect inhibition of phosphorylation of AKT.Quantitative results of phosphorylated AKT levels normalized to actinlevels (pAKT/actin) in samples from cells treated with increasingconcentrations of the tested compounds are presented in Table B1.Quantitative results of phosphorylated AKT levels normalized to actinlevels (pAKT/actin) in samples from cells treated with 1 nM, 10 nM, or100 nM of the tested compounds relative to the phosphorylated AKT levelsin samples from cells treated with 0.1 nM of the tested compounds arepresented in Table B2.

TABLE B1 Levels of phosphorylated AKT in treated cells. Compound nM No.Vehicle 0.1 1 10 100 OSI-906 0.00 1.06 0.85 1.58 0.40 BMS-754807 0.021.15 1.86 0.09 0.02  2 0.00 1.04 0.91 0.07 0.00  2a 0.06 1.70 1.78 1.811.72  2b 0.00 1.57 0.80 0.22 0.03  3a 0.00 2.64 1.68 1.86 2.19  3b 0.002.25 1.70 0.57 0.02  4 0.02 1.92 1.59 1.01 0.06  4a 0.00 2.38 1.64 1.761.47  4b 0.00 1.81 1.92 1.64 0.20  5 0.00 2.28 0.61 0.04 0.00  6 0.031.54 0.22 0.01 0.01  6a 0.00 1.85 1.74 1.40 1.17  6b 0.00 0.87 0.18 0.000.00  7 0.00 1.45 2.08 1.09 1.20  8a 0.05 1.93 2.27 1.17 1.78  8b 0.031.47 0.31 0.04 0.02  9 0.03 0.67 0.71 0.07 0.00  9a 0.00 1.24 1.26 0.530.02  9b 0.00 1.46 1.55 1.18 0.78 10a 0.00 2.28 0.54 0.00 0.01 10b 0.002.21 2.75 1.71 1.66 11a 0.00 1.83 1.55 1.43 1.58 11b 0.03 1.55 1.76 1.430.33 12a 0.17 4.17 3.33 2.91 4.16 12b 0.23 3.66 3.56 4.32 2.29 13a 0.000.51 0.54 0.45 0.80 13b 0.00 0.22 0.09 0.00 0.00 14a 0.00 0.73 0.51 0.430.35 14b 0.00 0.51 0.49 0.02 0.00 15a 0.00 0.70 0.89 0.92 0.59 15b 0.000.52 0.58 0.43 0.13 16a 0.00 0.82 0.62 0.61 0.30 16b 0.00 0.53 0.51 0.150.01 17a 0.00 0.89 1.22 1.01 1.08 17b 0.00 0.83 0.99 0.95 1.08

TABLE B2 Normalized phosphorylated AKT (relative to actin) levelsrelative to 0.1 nM compound treatment. Compound nM No. Vehicle 0.1 1 10100 OSI-906 0.0 1.0 0.8 1.5 0.4 BMS-754807 0.0 1.0 1.6 0.1 0.0  2 0.01.0 0.9 0.1 0.0  2a 0.0 1.0 1.0 1.1 1.0  2b 0.0 1.0 0.5 0.1 0.0  3a 0.01.0 0.6 0.7 0.8  3b 0.0 1.0 0.8 0.3 0.0  4 0.0 1.0 0.8 0.5 0.0  4a 0.01.0 0.7 0.7 0.6  4b 0.0 1.0 1.1 0.9 0.1  5 0.0 1.0 0.3 0.0 0.0  6 0.01.0 0.1 0.0 0.0  6a 0.0 1.0 0.9 0.8 0.6  6b 0.0 1.0 0.2 0.0 0.0  7 0.01.0 1.4 0.7 0.8  8a 0.0 1.0 1.2 0.6 0.9  8b 0.0 1.0 0.1 0.0 0.0  9 0.01.0 1.1 0.1 0.0  9a 0.0 1.0 1.0 0.4 0.0  9b 0.0 1.0 1.1 0.8 0.5 10a 0.01.0 0.2 0.0 0.0 10b 0.0 1.0 1.2 0.8 0.8 11a 0.0 1.0 0.8 0.8 0.9 11b 0.01.0 1.1 0.9 0.2 12a 0.0 1.0 0.8 0.7 1.0 12b 0.1 1.0 1.0 1.2 0.6 13a 0.01.0 1.1 0.9 1.6 13b 0.0 1.0 0.4 0.0 0.0 14a 0.0 1.0 0.7 0.6 0.5 14b 0.01.0 0.9 0.0 0.0 15a 0.0 1.0 1.3 1.3 0.8 15b 0.0 1.0 1.1 0.8 0.3 16a 0.01.0 0.8 0.7 0.4 16b 0.0 1.0 1.0 0.3 0.0 17a 0.0 1.0 1.4 1.1 1.2 17b 0.01.0 1.2 1.1 1.3 Compound p-AKT relative to levels with 0.1 nM compoundNo. Vehicle 0.1 nM 1 nM 10 nM 100 nM OSI-906 0.0 1.0 0.8 1.5 0.4BMS-754807 0.0 1.0 1.6 0.1 0.0  2 0.0 1.0 0.9 0.1 0.0  2a 0.0 1.0 1.01.1 1.0  2b 0.0 1.0 0.5 0.1 0.0  3a 0.0 1.0 0.6 0.7 0.8  3b 0.0 1.0 0.80.3 0.0  4 0.0 1.0 0.8 0.5 0.0  4a 0.0 1.0 0.7 0.7 0.6  4b 0.0 1.0 1.10.9 0.1  5 0.0 1.0 0.3 0.0 0.0  6 0.0 1.0 0.1 0.0 0.0  6a 0.0 1.0 0.90.8 0.6  6b 0.0 1.0 0.2 0.0 0.0  7 0.0 1.0 1.4 0.7 0.8  8a 0.0 1.0 1.20.6 0.9  8b 0.0 1.0 0.1 0.0 0.0  9 0.0 1.0 1.1 0.1 0.0  9a 0.0 1.0 1.00.4 0.0  9b 0.0 1.0 1.1 0.8 0.5 10a 0.0 1.0 0.2 0.0 0.0 10b 0.0 1.0 1.20.8 0.8 11a 0.0 1.0 0.8 0.8 0.9 11b 0.0 1.0 1.1 0.9 0.2 12a 0.0 1.0 0.80.7 1.0 12b 0.1 1.0 1.0 1.2 0.6 13a 0.0 1.0 1.1 0.9 1.6 13b 0.0 1.0 0.40.0 0.0 14a 0.0 1.0 0.7 0.6 0.5 14b 0.0 1.0 0.9 0.0 0.0 15a 0.0 1.0 1.31.3 0.8 15b 0.0 1.0 1.1 0.8 0.3 16a 0.0 1.0 0.8 0.7 0.4 16b 0.0 1.0 1.00.3 0.0 17a 0.0 1.0 1.4 1.1 1.2 17b 0.0 1.0 1.2 1.1 1.3

The compounds of the invention inhibited AKT phosphorylation withvarying degrees of efficacy and several proved more effective thaneither OSI-906 or BMS.

The effects of other derivatives of Cpd. No. 8b on AKT phosphorylationwere tested as described above.

Compound pAKT relative to 0.1 nM compound No. Vehicle 0.1 nM 1 nM 10 nM100 nM  5 0.01 1.00 0.59 0.08 0.03  6b 0.00 1.00 0.39 0.02 0.01 10a 0.011.00 0.69 0.16 0.01 10d 0.00 1.00 0.84 0.23 0.01 13b 0.03 1.00 0.49 0.040.02

Example B2 In Vitro IGF-1R and IR Enzymatic Assays

IC₅₀ values of the compounds of the invention against IGF-1R and IR weremeasured in vitro using an ADP-Glo kinase assay Kit (Promega). For theIGF-1R assay, active recombinant IGF-1R (Millipore #14-802) was used at1 ng/reaction, the substrate IGF-1R tide (Millipore #12-527) was used at125 μM and ATP was used at 100 μM. For the IR assay, active recombinantIR (Millipore #14-803) as used at 1 ng/reaction, the substrate Ax1 tide(Millipore #12-516) was used at 125 μM and ATP at 50 μM. Kinasereactions in both assays were conducted at 30° C. for 20 min withincreasing concentrations of compounds of the invention.

The IC₅₀ values of Compound nos. 2b & 8b, and BMS-754807 against IGF-1Rand IR are listed in Tables B3 and B4, respectively.

TABLE B3 IC₅₀ Values of Compound nos. 2b & 8b, and BMS-754807 againstIGF-1R. Compound Hill Slope IC₅₀ (M) No. N1 N2 N1 N2 2b 1.195 1.3847.239E−09 5.29E−09 8b 1.042 1.307 3.108E−09 5.49E−09 BMS 754807 1.1761.123 1.673E−08 1.91E−08

TABLE B4 IC₅₀ Values of Compound nos. 2b & 8b, and BMS-754807 againstIR. Compound Hill Slope IC₅₀ (M) No. N1 N2 N1 N2 2b 1.34 1.13 5.51E−094.07E−09 8b 0.96 1.19 3.95E−09 3.60E−09 BMS 754807 1.16 1.05 2.35E−082.50E−08

The compounds of the invention were screened against activated IGF-1R ata concentration of 3.00×10⁻⁸ M in duplicate. The assay results arepresented as the percent inhibition of binding in Table B5.

TABLE B5 Percent Inhibition of Binding against Activated IGF-1R, andselected IC₅₀ values. Compound % Inh @ 30 nM No. (N1) (N2) Avg IC₅₀ (nM) 2a −12 18 3  2b 90 88 89 6.1  4a 4 17 10  4b 22 35 28  5 66, 79 13, 17 6a 22 33 28  6b 93 95 94 6.5  8a 0  8b 93 95 94 5.1  9b 14 17 16 11a 1710 13 10a 32 33.0 10b −11 10c 15 10d 84 5.8 11b 22 11 17 12a 19 20 2012b 13 34 24 13a 10 34 22 13b 82 80 81 17 14b 77 76 77 22 15a 17 20 1915b 32 28 30 16a 27 15 21 16b 40 40 40 17a 12 24 18 17b 21 23 22 18a 1418b 39 19a −3 19b 21 20a 11 20b 9 21a 14 21b 41 50  35

The compounds of the invention were screened against activated IR at aconcentration of 3.00×10⁻⁸ M in duplicate. The assay results arepresented as the percent inhibition of binding in Table B6.

TABLE B6 Percent Inhibition of Binding against Activated IR. Compound %Inh @ 30 nM No. (N1) (N2) Avg IC₅₀ (nM)  2a 0 10 5  2b 92 88 90 5.7  4a−14 −2 −8  4b 41 33 37  5 76, 88 8.3, 12.0  6a −13 9 −2  6b 92 91 9241.3  8b 91 89 90 5.45  9b 3 9 6 10a 54 33.0 10d 85 7.2 11a −17 −9 −1311b −2 9 3 12a 10 8 9 12b −14 −10 −12 13a 4 −1 2 13b 84 80 82 13 14b 8281 81 16 15a −2 4 1 15b 28 31 30 16a 1 −7 −3 16b 26 23 25 17a 2 5 3 17b2 10 6 18a 3 18b 32 19a −9 19b 9 21b 30 120.0 50 51 36.0 68 11.0 69 32.070 22.0 71 44.0 72 16.0

The binding data of the compounds of the invention to IGF-1R and IRreflect the efficacy of the compounds in inhibiting the phosphorylationof AKT as demonstrated in Example 1.

Example B3 Kinome Analysis Example B3A Screening of Compound Nos. 2b&8b, BMS-754807, and OSI-906 Against a Panel of 192 Kinases

A kinase profiling study of compound 8b was conducted by CaliperLifeSciences Services (Hanover, Md.). The compound was tested atconcentrations of 1.0×10⁻⁸ and 1.0×10⁻⁹ M in the RapidKinase192™ panelin duplicate. The following kinases were assessed in the panel: ABL;Abl(H396P); Abl(Q252H); Abl(T315I); ABL1(E255K); ABL1(G250E);ABL1(Y253F); AKT1; AKT2; AKT3; ALK; AMPK; AMPK-alpha2/beta1/gamma1; Arg;AurA; AurB; AurC; AXL; BLK; BMX; BRSK1; BRSK2; BTK; CaMK1a; CamK1d;CAMK2; CaMK2a; CAMK4; CaMKII beta; CaMKII gamma; Casein kinase 1g2;CDK1/Cycline B1; CDK2; CDK3; CDK5/p25; CHK1; CHK2; CK1d; CK1-epsilon;CK1g3 (CSNK1G3); CK1-gamma1; CLK2; c-Raf; CSNK1A1; c-TAK1; DAPK1;DCAMKL1; DCAMKL2; DDR2; DYRK1a; DYRK1B; DYRK3; DYRK4; EGFR; EGFR (ErbB1)T790M L858R; EGFR(T790M); EPHA1; EPHA2; EPHA3; EPHA4; EPHA5; EPHA8;EPHB1; EPHB2; EPHB3; EPHB4; Erk1; Erk2; Fer; FES; FGFR1; FGFR1 (V561M);FGFR2; FGFR2(N549H); FGFR3; FGFR3 [K650E]; FGFR4; FGR; FLT1; FLT3;Flt3(D835Y); FLT4; FMS; FRK; FYN; GCK; GSK3-alpha; GSK3b; Hck; HER4;HGK; HIPK1; HIPK2; IGF1R; IKBKE (IKK epsilon); IKK-beta; INSR; IRAK4;ITK; JAK2; KDR; KIT; KIT[T670I]; LCK; LOK; LTK; LYN; LYNB; MAPKAPK2;MAPKAPK3; MARK1; MARK2; MARK4; MELK; Mer; MET; MET M1250T; MINK; MNK1(MKNK1); MSK1; MSK2; MST1; MST1R; MST2; MST3 (STK24); NEK1; NEK2; NTRK2(TRKB); NuaK1; p38a; p38alpha/SAPK2a (T106M); p38-beta2; p38-delta;p38-gamma; p70S6K; PAK2; PAK3; PAK4; PAK5 (PAK7); PASK; PDGFR beta;PDGFR_alpha; PDGFRA (D842V); PDGFR-alpha (V561D); PhKg1; PhKg2; PIM1;PIM2; PIM3; PKA; PKC-alpha; PKCb2; PKC-beta1; PKC-delta; PKC-epsilon;PKC-eta; PKC-gamma; PKC-theta; PKCz; PKD1; PKD2; PKD3; PKG1-beta; PKGa;PRAK; PRKCI (PKC-iota); PRKX; PYK2; RET; Ret (V804L); RET; Y791F; ROCK1;ROCK2; ROS(ROS1); RSK1; RSK2; RSK3; RSK4; SGK1; SGK2; SGK3; SRC; SRM(SRMS); SYK; TEC; TRKC (NTRK3); TSSK1; TSSK2; TXK; TYRO3; YES; and ZIPK(DAPK3). The screening was performed using the Caliper EZReader2, a4-sipper LabChip, and ProfilerPro Kinase Selectivity Assay Kits 1 and 2.The assay measures the conversion of a fluorescent peptide substrate toa phosphorylated product. Briefly, the reaction mixture was introducedthrough a capillary sipper onto the microfluidic chip, where thesubstrate and product were electrophoretically separated and detected bylaser-induced fluorescence. The time-dependent fluorescence signalindicates the extent of the reaction. The extent of binding wasclassified into three main groups: Low (39% or lower inhibition), Medium(40 to 59% inhibition) and High (60% or higher inhibition).

For Compound No. 8b, it was found that all binding was Low at both 1 nMand 10 nM concentration, with the exception of the following (+=Low,++=Med, +++=High) as shown in Table B7.

TABLE B7 Kinase binding of Compound No. 8b. Average % Inh @ 1 nM Average% Inh @ 10 nM Kinase Compound No. 8b IGF-1R + +++ AXL + ++ INSR ++ +++Mer + +++ MET + ++ NTRK2(TRKB) +++ +++ PYK2 + ++ ROS (ROS1) ++ +++TRXC(NTRK3) +++ +++

Kinase profiling studies of Compound no. 2b, BMS-754807, and OSI-906were also conducted as described above using a single concentration of 1μM.

For Compound no. 2b, it was found that all binding was Low with theexception of the following (++=Med, +++=High) as shown in Table B8:

TABLE B8 Kinase binding of Compound No. 2b. Average % Inh @ 1 μM KinaseCompound No. 2b ABL ++ Abl(H396P) ++ Abl(Q252H) ++ Abl(T315I) +++ABL1(G250E) +++ ABL1(Y253F) ++ ALK +++ AMPK +++ AMPK-α2/β1/γ1 +++ Arg+++ AurA, B, C +++ AXL +++ BLK +++ BMX ++ BTK ++ DCAMKL1 ++ DCAMKL2 +++DDR2 +++ EPHA1, 2 +++ EPHA3 ++ EPHA4 ++ EPHA5 +++ EPHB1 +++ EPHB2 +++EPHB4 ++ Fer +++ FES ++ FGFR1 +++ FGFR1(V561M) +++ FGFR2 +++FGFR2(N549H) +++ FGFR3 +++ FGFR3(K650E) +++ FGR +++ FLT3 ++ Flt3(D835Y)+++ FLT4 ++ FRK +++ FYN +++ Hck +++ IGF1R +++ INSR +++ ITK ++ JAK2 +++KDR ++ LCK +++ LTK +++ LYN +++ LYNB +++ Mer +++ MET +++ MET(M1250T) +++MST1, 1R, 2 +++ NTRK2(TRKB) +++ NuaK1 +++ PAK5(PAK7) ++ PhKg2 ++ PYK2+++ RET +++ Ret(V804L) +++ RET(Y791F) +++ ROS(ROS1) +++ SRC +++TRXC(NTRK3) +++ TYRO3 +++ Yes +++

In particular cases of high inhibition at 1 μM, testing was continued atconcentrations of 10 nM and 100 nM, with the following results obtained(+=Low, ++=Med, +++=High) as shown in Table B9:

TABLE B9 Kinase binding of Compound No. 2b at 10 nM and 100 nM. Compoundno. 2b Average Average % Inh @ % Inh @ Kinase 10 nM 100 nMAbl(T315I) + + ALK + + AMPK + ++ AMPK-α2/β1/γ1 + ++ Arg + + AurA + +++AurB ++ +++ AurC +++ +++ AXL ++ +++ BLK + + BMX + + EPHA1 + ++ Fer + +++FGFR1 + + FGFR1(V561M) + ++ FGFR2 + + FGFR2(N549H) + + FGR + + FYN + +++Hck + ++ IGF1R + ++ INSR + +++ LCK + + LYN + ++ LYNB + ++ Mer ++ +++MET + +++ MET M1250T + + MST1 + ++ MST2 + + NTRK(TRKB) +++ +++ NuaK1 +++ PYK2 + +++ RET + ++ Ret(V804L) + ++ RET(Y791F) + ++ ROS(ROS1) +++ +++SRC + +++ TRKC(NTRK3) +++ +++ TYRO3 + + Yes + ++

For BMS-754807, it was found that all binding was Low with the exceptionof the following (++=Med, +++=High) as shown in Table B10:

TABLE B10 Kinase binding of BMS-754807. Kinase Average % Inh @ 1 μMKinase BMS-754807 Abl(T315I) +++ ALK +++ AMPK +++ AMPK-α2/β1/γ1 +++ Arg++ AurA, B, C +++ AXL +++ BLK ++ BMX +++ c-TAK1 +++ DCAMKL1 +++ DCAMKL2+++ DDR2 +++ EPHA1, 2 +++ EPHA4 ++ EPHA5 ++ EPHB1 +++ EPHB2 ++ EPHB4 ++Fer +++ FES +++ FGFR1 +++ FGFR1(V561M) +++ FGFR2 +++ FGFR2(N549H) +++FGFR3 +++ FGFR3(K650E) ++ FGR +++ FLT3 ++ Flt3(D835Y) ++ FRK ++ FYN +++Hck +++ IGF1R +++ INSR +++ ITK +++ JAK2 +++ LCK ++ LTK ++ LYN ++ LYNB ++MARK1 ++ MARK2, 4 +++ Mer +++ MET +++ MET(M1250T) +++ MST1, 1R, 2 +++MST3 ++ NTRK2(TRKB) +++ NuaK1 +++ PAK5(PAK7) +++ PhKg2 ++ PYK2 +++ RET+++ Ret(V804L) +++ RET(Y791F) +++ ROS(ROS1) +++ SRC +++ TRXC(NTRK3) +++TYRO3 ++ Yes ++

In particular cases of high inhibition at 1 μM, testing was continued atconcentrations of 10 nM and 100 nM, with the following results obtained(+=Low, ++=Med, +++=High) as shown in Table B11:

TABLE B11 Kinase binding of BMS-754807 at 10 nM and 100 nM. BMS-754807Average Average % Inh @ % Inh @ Kinase 10 nM 100 nM AMPK + ++AMPK-α2/β1/γ1 + ++ AurA +++ +++ AurB +++ +++ AurC +++ +++ AXL + ++BMX + + DCAMKL1 + + DCAMKL2 + ++ DDR2 + ++ EPHA1 + ++ EPHA2 + + Fer ++++ FES + + FGFR1 + + FGFR1(V561M) + ++ FGFR2 + + IGF1R + +++ INSR +++++ Mer + ++ MET + +++ MET M1250T + ++ MST1 + + MST1R + + NTRK(TRKB) ++++++ PYK2 + +++ ROS(ROS1) +++ +++ TRKC(NTRK3) +++ +++

For OSI-906, it was found that all binding was Low with the exception ofthe following (++=Med, +++=High) as shown in Table B12:

TABLE B12 Kinase binding of OSI-906. Average % Inh @ 1 μM Kinase OSI-906IGF-1R +++ INSR +++ KDR ++

For Compound 8a, an enantiomer of Compound 8b, kinome profiling of 192kinases was also conducted but it was found that inhibition of allkinases was Low (<20% inhibition).

Compounds 2b and 8b were found to bind with high affinity to only a fewkinases, including IGF-1R and IR. The compounds did not bind with highaffinity to targets that are known to be associated with adversedownstream effects, such as AURA, AURB and AURC. However, the compoundsdid bind to targets such as TrkC, Mer, Met and AXL, which may bebeneficial because some of these kinases have been implicated intumorigenesis and cancer progression.

Compound 8b and several derivatives were tested by Caliper LifeSciencesServices (Hanover, Md.) against a panel of 11 kinases at three differentconcentrations, 0.1 μM, 0.01 μM and 0.001 μM. The kinases tested wereAurA, AurB, AurC, AXL, FAK2, IGF1R, InsR, Mer, MET, TrkB and TrkC. At0.1 μM, many of the compounds strongly inhibited most of the kinases.However, at 0.01 μM, only Compounds 5, 6b, 10a and 10d stronglyinhibited AXL, FAK2, TrkB and TrkC. These kinases have been reported tobe involved in tumorigenesis and cancer progression. These compounds andderivatives could be used to specifically target these four kinases andnot target other kinases such as AURA, AURB and AURC, the inhibition ofwhich is associated with adverse effects. At the lowest concentration(0.001 μM) none of the compounds inhibited the kinase more than 40%.

Example B3B Screening of Compound No. 8b Against Select Panel of 9Kinases

Kinase assays were performed using the top 9 kinases identified from thepanel of 192 kinases against Compound no. 8b. The assays were conductedby Caliper LifeSciences Services (Hanover, Md.) using Compound No. 8bover a range of 8 concentrations from 3.0×10⁻⁷ to 1.0×10⁻¹⁰ M induplicate. The assays were conducted using the Caliper LabChip 3000 anda 12-sipper LabChip as described above. The assay results are presentedas IC₅₀ values in Table B13.

TABLE B13 IC₅₀ values of Compound No. 8b and BMS-754807 against selectpanel of nine kinases. Kinase Compound No. 8b IC₅₀ (nM) BMS-754807 IC₅₀(nM) AXL 9.756 74.02 AURA 131.7 29.91 AURB 74.69 57.33 AURC 41.37 2.698FAK2(PTK2b) 2.361 4.346 Mer 3.840 79.56 Met 7.743 16.07 TrkB 12.21 7.022TrkC 3.002 3.259

ROS1 is a proto-oncogene and is highly expressed in many cancers. Thebinding of Compound 8b and BMS-754807 was measured by CaliperLifeScience Services (Hanover, Md.) as described above. Compounds weretested over a range of concentrations, from 0.03 nM to 1 and the IC50was calculated.

Kinase Compound No. 8b IC₅₀ (nM) BMS-754807 IC₅₀ (nM) ROS1 15 8.91

Example B4 Extended Panel Screen Against Non-Kinase Targets

Compound no. 8b was screened against a panel of 72 non-kinase targetsshown in Table B14. The experiments were performed by RicercaBiosciences (Painesville, Ohio) using the LeadProfilingScreen and CYP450assays. Compound no. 8b was screened at a concentration of 1 μM. Nosignificant hits were identified. The percent inhibition of allnon-kinase targets was under 30 percent inhibition, with the compoundexhibiting a percent inhibition of under 10 percent inhibition for over50 of the non-kinase targets tested.

TABLE B14 Non-Kinase Targets Non-Kinase Targets CYP₄₅₀ (1A2, 2C19, 2C9,3D6, 3A4), Adenosine (A₁, A_(2A), A₃), Adrenergic (α_(1A), α_(1B),α_(1D), α_(2A), β₁, β₂), Androgen (Testosterone) AR, Bradykinin (B₁,B₂), Ca-Channel (L-Type, N-Type), Cannabinoid CB₁, Dopamine (D₁, D_(2S),D₃, D_(4.2)), Endothelin (ET_(A), ET_(B)), Epidermal Growth Factor(EGF), Estrogen ERα, GAB A (A, B1A), Glucocorticoid, Glutamate(Kainate), Glutamate NMDA (Agonist, Glycine, Phencyclidine), Histamine(H₁, H₂, H₃), Imidazoline I₂ Central, Interleukin IL-1, LeukotrieneCysLT₁, Melatonin M₁, Muscarinic (M₁, M₂, M₃), Neuropeptide (Y₁, Y₂),Nicotinic (Acetylcholine, α1), Opiate (δ₁, κ, μ), Phorbol Ester,Platelet Activating Factor, Potassium Channel (K_(ATP), hERG),Prostanoid EP₄, Purinergic (P_(2X), P_(2Y)), Rolipram, Serotonin(5-HT_(1A), 5-HT_(2B), 5-HT₃), Sigma σ₁, Tachykinin NK₁, ThyroidHormone, Transporter (Dopamine DAT, GABA, Norepinephrine NET, SerotoninSERT.

Example B5 Cell Viability Studies

Compound nos. 2b & 8b, OSI-906 and BMS-754807 were screened against apanel of 10 cancer cell lines (BT-20, HCC 1187, LNCaP, MCF-7, MDA MB175, MDA MB 231, OVCAR-3, T47D, UACC 812, and ZR-75-1). This panel ofcell lines includes an ER− breast carcinoma, primary breast ductalcarcinoma, prostate adenocarcinoma, mammary adenocarcinoma, mammaryductal carcinoma, mammary ductal carcinoma, ovary adenocarcinoma, ER+breast carcinoma, ER-HER2+ mammary ductal carcinoma and an ER+ mammaryductal carcinoma, respectively.

This study was conducted by Caliper LifeSciences Services (Hanover, Md.)using the Cell Titer-Glo® assay to determine inhibition of cellproliferation. This assay quantitates the ATP present in order todetermine the number of viable cells in culture. Briefly, the compoundswere incubated with the cells for 72 h, followed by cell lysis. Theresulting luminescent signal is proportional to the amount of ATPpresent and, therefore, directly proportional to the number of cellspresent in culture. The compounds were studied over a range of 10concentrations from 1×10⁻⁴ to 5×10⁻⁹M in duplicate and IC₅₀ values werecalculated. The maximum concentration used in the dose range for IC₅₀determination was 1×10⁻⁶M. Compound No. 8b inhibited proliferation inall cell lines tested.

Compound nos. 2b & 8b, OSI-906, and BMS-754807 were further screened byCaliper LifeSciences against an additional panel of 7 cell lines (A549,COLO 205, HCT-15, HCT-116, HL-60, HT-29, SW-620) using the assaydescribed above. These cell lines are derived from human lung carcinoma,colon adenocarcinoma, colon adenocarcinoma, colon carcinoma, acutepromyelocytic leukemia, colon adenocarcinoma, colon adenocarcinoma (frommetastatic site lymph node), respectively.

The assay results are presented as calculated IC₅₀ values in Table B15.Compound nos. 2b & 8b displayed more potent effects in all cell linestested than either OSI or BMS.

TABLE B15 IC₅₀ values for Compound Nos. 2b & 8b, OSI-906 and BMS-754807tested in cell viability assays. Compound Compound No. 2b No. 8b OSI-906BMS-754807 Cell Line Tissue IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) HT-29colon cancer 0.5 <0.01 <100 <10 HL-60 promyelocytic <10 0.01 <100 <10leukemia A549 non-small lung 1 <10 10 <10 carcinoma COLO-205 colon <0.01<0.01 1 <1 adenocarcinoma HCT15 colon carcinoma <10 <10 <100 <100 HCT116colon carcinoma 1 1 <100 10 HL60 promyelocytic <0.01 <0.01 <10 <10leukemia HT29 colon <0.01 <0.01 <10 <1 adenocarcinoma SW-620 metastatic0.1 1 <100 1 colorectal cancer BT20 breast cancer <10 <100 LNCaPprostate cancer <10 <10 MCF7 breast cancer <10 0.1 T47D breast cancer <1<10 MDAMB175 breast cancer <10 <100 MDAMB231 breast cancer 10 <10 OVCAR3ovarian cancer 1 <10 UACC812 breast cancer <10 <100 HCC1187 breastcancer <10 <10 ZR-75-1 breast cancer <100 >100

Compounds 2b, 5, 6b and 10a were tested along with derivatives inviability assays as described above by Caliper LifeSciences Systems(Hanover, Md.), in A549, HCT-15, HCT-116, MCF-7, MDA-MB-231, OVCAR3,T47D, COLO205, HT-29, BT-20, HCC1187, HL-60, MDA-MB-175, SW-620, andUACC812 cells. IC₅₀ values were calculated as before, and are presentedin Table B16.

TABLE B16 IC₅₀ values for Compound Nos. 2b 5, 6b and 10a tested in cellviability assays. Compound Compound Compound Compound No. 2b No. 5 No.10a No. 6b Cell Line Tissue IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) A549non-small lung <1 <1 <10 <1 carcinoma HCT15 colon 1 <10 <100 1 carcinomaHCT116 colon 1 <10 10 <1 carcinoma MCF7 breast cancer 1 <1 <1 <1MDAMB231 breast cancer 1 <10 10 <1 OVCAR3 ovarian cancer <1 <1 1 <0.1T47D breast cancer 1 <1 1 <1 COLO205 colon cancer <0.1 0.1 <0.1 <0.1HT-29 colon <0.01 0.01 <0.1 <0.01 adenocarcinoma BT-20 breast cancer 1<10 <10 1 HCC-1187 breast cancer 0.1 <1 <1 <1 HL60 promyelocytic <1 <0.10.1 <1 leukemia LNCaP Prostate cancer <1 0.1 <1 0.1 MDA-MB-175 breastcancer <10 1 <10 <1 SW-620 metastatic <1 <1 <10 <1 colorectal cancerUACC 812 breast cancer <10 <100 <10 1

The inhibitory effects of Compound 8a were tested in two cell lines. Theproliferation of the breast cancer cell lines MDA-MB-175 and UACC812 didnot drop below 68% as compared to the untreated control with anyconcentration of compound tested (3 μM was the maximum concentrationtested).

Analogous studies utilizing pancreatic cancer cell lines such as ASPC-1and PANC-1 can be performed with compounds of the invention. In oneexample, Compound 8b gave IC₅₀ values of 0.195 uM and 3.663 uM,respectively.

Example B6A Efficacy in Xenograft Model

To evaluate the efficacy of tumor growth inhibition, the compound 8b wasstudied using human cancer mouse models. The models are prepared bysubcutaneously or orthotopically implanting mice with human cancercells. When the tumor size of the mice develops (e.g., reaches 100 mm³),the mice are divided into groups for treatment with compound 8b (wheredifferent groups receiving the compound 8b may be administered differentamounts of the compound 8b) or are provided no compound as a control.The mice are treated (e.g., orally administered a compound of theinvention) for a period of time. During the course of the study, thetumor is measured and the weight of the mice is determined. After thetreatment period, the mice are sacrificed shortly (e.g. 1 or 2 hours)after the final dose. Blood and tissue are collected for biochemicalanalysis.

Example B6B Efficacy in Xenograft Model of Human Colon Cancer

To evaluate the efficacy of tumor growth inhibition, compound 8b wasstudied using a human colon cancer mouse model. The model is prepared bysubcutaneously implanting 50 nude, male 5-6 week old mice withapproximately 4×10⁶ viable human colon cancer COLO-205 cells. When thetumor size reached 100 mm³, the mice were divided into 5 groups (10mice/group) for treatment with 0, 1, 3, 10, and 15 mg/kg of compound 8b.As detailed in the FIGS. 1 and 3, the 10 and 15 mg/kg group were treatedwith 3 days of drug holiday and all other groups were treated daily.Tumor volume and mouse body weight were monitored over the 20 dayexperiment. A Kruskal-Wallis ANOVA test was used to determinestatistical significance of tumor volume measurements.

Example B6C Efficacy in Xenograft Model of Human Breast Cancer

To evaluate the efficacy of tumor growth inhibition, compound 8b wasstudied using a human breast cancer mouse model. The model was preparedby orthotopic implanting 50 nude, female 5-6 week old mice withapproximately 2×10⁶ viable human breast cancer MCF7 cells supplementedwith estrogen pellets (1.5 mg 60 day slow release). When the tumor sizereached 100 mm³, the mice were divided into 5 groups (10 mice/group) fortreatment with 0 and 10 mg/kg/po daily; 10 and 15 mg/kg/po every otherday; and 15 mg/kg/po with 2 days on and 2 days off, of compound 8b.

The appropriate amount of compound 8b was sonicated in a PEG-400solution (80% w/v in case of Example B6B; and 50% w/v in case of ExampleB6C) to completely dissolve the compound, followed by dropwise additionof the required amount of H₂O. The resulting 250 μL dose volume (10mL/kg) was administered orally to the mouse. During the course of thestudy, the tumor was measured and the weight of the mice was determined.

At the end of the study, the mice were sacrificed at 2 h (Example B6B)and at 1 h (Example B6C) after the final dose. Blood and tissue werecollected for biochemical analysis.

Compound 8b dose-dependently and significantly reduced tumor burden inthe COLO205 colon cancer model (FIG. 1) as well as in the MCF7 breastcancer model (FIG. 2). This was well supported by tumor weight andcompound 8b exposure levels measured at the end of the each study.Compound 8b dose-dependently reduced body weights of the mice during theinitial part of the study but they did recover from their weight lossmarginally in the latter part of the study (FIG. 4) or when drug holidaywas given (FIGS. 3 and 4).

Any noted weight loss or/and hyperglycemia can be managed by giving adrug holiday and/or treatment with antihyperglycemic drugs (e.g. insulinor metformin or other appropriate antidiabetic drug) as needed.

Analogous studies with compounds of the invention can be performed withfurther dosing regimens including, for example treatment with testcompound at <10 mg/kg such as 5 mg/kg, or >15 mg/kg such as 30 mg/kg,and at varied time points such as daily, every other day, etc.Similarly, activity of compounds of the invention in alternative celltypes such as pancreatic cancer AsPC-1 cells can be assessed in similarfashion to those described above.

Example B7 Cell Screens for Cancer Types and Subtypes

Cancer cells are grown according to recommended culture conditions. Toevaluate cell viability, cells are plated and allowed to attachovernight. The cell density is adjusted so that the cells will be 70-80%confluent at the end of the assay. After cell attachment, the medium isremoved and replaced with fresh medium containing test compound atdifferent concentrations. Test compound is diluted from a DMSO stocksuch that the final DMSO concentration in the assay is 0.2%. Seventy-twohours after exposing cells to test compound, cell viability is evaluatedusing a cell viability assay such as CellTiter Glo™ (Promega, Madison,Wis.), and IC₅₀ values are determined.

Cancer cell types that may be used in this assay include, withoutlimitation, bladder cancer, breast cancer, colorectal cancer,endometrial cancer, hematopoietic cancer, liver cancer, lung cancer,ovarian cancer, pancreatic cancer, and prostate cancer cells. Breastcancer cell types include, without limitation, HER2 positive breastcancer, luminal breast cancer, triple negative breast cancer (e.g.,basal, mesenchymal, mesenchymal stem-like, immunomodulatory, and luminalandrogen receptor subtypes), and unclassified breast cancer cells. Livercancer cell types include, without limitation, hepatitis B virus-derivedliver cancer and virus-negative liver cancer cells. Lung cancer celltypes include, without limitation, non-small cell lung carcinoma, smallcell lung carcinoma, adenocarcinoma, mucoepidermoid, anaplastic, largecell, and unclassified lung cancer cells.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

The invention claimed is:
 1. A compound of the formula (I):

or a salt or N-oxide thereof, wherein: D is hydrogen; unsubstitutedC₁-C₆ alkyl; C₁-C₆ alkyl substituted by 1 to 5 substituentsindependently selected from the group consisting of hydroxy, heteroaryl,and heteroaryl substituted by C₁-C₆ alkyl; unsubstituted aryl;unsubstituted heteroaryl; heteroaryl substituted by 1 to 5 substituentsindependently selected from the group consisting of alkoxy, amino, halo,hydroxy and thioalkyl; unsubstituted C₃-C₈ cycloalkyl; unsubstitutedheterocyclyl; or heterocyclyl substituted by 1 to 5 substituentsindependently selected from unsubstituted acyl, acyl substituted byamino, C₁-C₆ alkyl and oxo; wherein the heteroaryl of D is selected fromthe group consisting of pyridyl, pyrimidyl, pyrazinyl, thiazolyl,oxazolyl, pyrazolyl, furanyl and thiadiazolyl, and the heterocyclyl of Dis selected from the group consisting of pyrrolidinyl and piperidinyl; Eis unsubstituted 5-membered heteroaryl or 5-membered heteroarylsubstituted by 1 to 4 substituents independently selected from the groupconsisting of unsubstituted acylamino, hydroxy, unsubstituted C₁-C₆alkyl, C₁-C₆ alkyl substituted by hydroxy, unsubstituted C₃-C₈cycloalkyl, and C₃-C₈ cycloalkyl substituted by hydroxy or C₁-C₆ alkyl;each j, k, m, and n is independently 0 or 1; each R^(A1), R^(A2),R^(A3), R^(A4), R^(A5), R^(A6), R^(A7), R^(A8), R^(A9) and R^(A10),where present, is independently hydrogen, unsubstituted C₁-C₆ alkyl,halo, hydroxy, or taken together with a geminal R^(A(1-10)) group andthe carbon to which they are attached to form a carbonyl moiety or athiocarbonyl moiety; R^(D) is hydrogen; X is O or S; R^(Z) is hydrogen,or unsubstituted C₁-C₆ alkyl; each R^(Z1) and R^(Z2) is independentlyhydrogen, or unsubstituted C₁-C₆ alkyl; each R^(Z3), R^(Z4), R^(Z5),R^(Z6), R^(Z7) and R^(Z8), where present, is independently hydrogen,unsubstituted C₁-C₆ alkyl, halo, hydroxy, —OR¹, —O—C₁-C₆alkylene-P(O)(OH)₂, —OC(O)R⁸, unsubstituted tetrazolyl, tetrazolylsubstituted by C₁-C₆ alkyl, or is taken together with a geminalR^(Z(3-8)) group and the carbon to which they are attached to form acarbonyl moiety; each R¹ is independently unsubstituted C₁-C₆ alkyl;each R⁸ is independently unsubstituted C₁-C₆ alkyl.
 2. The compound ofclaim 1, or a salt or N-oxide thereof, wherein each of j and k is
 0. 3.The compound of claim 2, or a salt or N-oxide thereof, wherein each ofR^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) is hydrogen.
 4. Thecompound of claim 2, or a salt or N-oxide thereof, wherein each ofR^(A1) and R^(A2) is independently C₁-C₆ alkyl; and each of R^(A3),R^(A4), R^(A5) and R^(A6) is hydrogen.
 5. The compound of claim 4, or asalt or N-oxide thereof, wherein each of R^(A1) and R^(A2) is methyl. 6.The compound of claim 2, or a salt or N-oxide thereof, wherein each ofR^(A3) and R^(A4) is independently C₁-C₆ alkyl; and each of R^(A1),R^(A2), R^(A5) and R^(A6) is hydrogen.
 7. The compound of claim 6, or asalt or N-oxide thereof, wherein each of R^(A3) and R^(A4) is methyl. 8.The compound of claim 2, or a salt or N-oxide thereof, wherein each ofR^(A5) and R^(A6) is independently C₁-C₆ alkyl; and each of R^(A1),R^(A2), R^(A3) and R^(A4) is hydrogen.
 9. The compound of claim 8, or asalt or N-oxide thereof, wherein each of R^(A5) and R^(A6) is methyl.10. The compound of claim 2, or a salt or N-oxide thereof, wherein eachof R^(A1), R^(A2), R^(A5) and R^(A6) is hydrogen.
 11. The compound ofclaim 2, or a salt or N-oxide thereof, wherein each of R^(A5) and R^(A6)is hydrogen.
 12. The compound of claim 2, or a salt or N-oxide thereof,wherein R^(A3) and R^(A4) are taken together with the carbon to whichthey are attached to form a carbonyl moiety; and each of R^(A1), R^(A2),R^(A5) and R^(A6) is hydrogen.
 13. The compound of claim 2, or a salt orN-oxide thereof, wherein R^(A3) and R^(A4) are taken together with thecarbon to which they are attached to form a thiocarbonyl moiety; andeach of R^(A1), R^(A2), R^(A5) and R^(A6) is hydrogen.
 14. The compoundof claim 2, or a salt or N-oxide thereof, wherein each of R^(A3) andR^(A4) is independently halogen; and each of R^(A1), R^(A2), R^(A5) andR^(A6) is hydrogen.
 15. The compound of claim 14, or a salt or N-oxidethereof, wherein each of R^(A3) and R^(A4) is fluorine.
 16. The compoundof claim 2, or a salt or N-oxide thereof, wherein R^(A3) is halogen; andeach of R^(A1), R^(A2), R^(A4), R^(A5) and R^(A6) is hydrogen.
 17. Thecompound of claim 16, or a salt or N-oxide thereof, wherein R^(A3) isfluorine.
 18. The compound of claim 2, or a salt or N-oxide thereof,wherein each of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) isindependently hydroxy or hydrogen.
 19. The compound of claim 18, or asalt or N-oxide thereof, wherein one of R^(A1), R^(A2), R^(A3), R^(A4),R^(A5) and R^(A6) is hydroxy.
 20. The compound of claim 18, or a salt orN-oxide thereof, wherein two of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5)and R^(A6) are hydroxy.
 21. The compound of claim 1, or a salt orN-oxide thereof, wherein j is 1 and k is
 0. 22. The compound of claim21, or a salt or N-oxide thereof, wherein each of R^(A1), R^(A2),R^(A3), R^(A4), R^(A5), R^(A6), R^(A7) and R^(A8) is hydrogen.
 23. Thecompound of claim 1, or a salt or N-oxide thereof, wherein each of j andk is
 1. 24. The compound of claim 23, or a salt or N-oxide thereof,wherein each of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5), R^(A6), R^(A7),R^(A8), R^(A9) and R^(A10) is hydrogen.
 25. The compound of claim 1, ora salt or N-oxide thereof, wherein each of m and n is
 0. 26. Thecompound of claim 25, or a salt or N-oxide thereof, wherein each ofR^(Z1), R^(Z2), R^(Z3) and R^(Z4) is hydrogen.
 27. The compound of claim1, or a salt or N-oxide thereof, wherein m is 1 and n is
 0. 28. Thecompound of claim 27, or a salt or N-oxide thereof, wherein each ofR^(Z1), R^(Z2), R^(Z3) and R^(Z4) is hydrogen.
 29. The compound of claim27, or a salt or N-oxide thereof, wherein each of R^(Z5) and R^(Z6) ishydrogen.
 30. The compound of claim 27, or a salt or N-oxide thereof,wherein R^(Z5) is hydroxy; and R^(Z6) is hydrogen.
 31. The compound ofclaim 27, or a salt or N-oxide thereof, wherein R^(Z3) is hydroxy; andR^(Z4) is hydrogen.
 32. The compound of claim 27, or a salt or N-oxidethereof, wherein R^(Z5) is OR¹; and R^(Z6) is hydrogen.
 33. The compoundof claim 32, or a salt or N-oxide thereof, wherein R^(Z5) is methoxy.34. The compound of claim 27, or a salt or N-oxide thereof, whereinR^(Z5) is halogen; and R^(Z6) is hydrogen.
 35. The compound of claim 34,or a salt or N-oxide thereof, wherein R^(Z5) is fluorine.
 36. Thecompound of claim 27, or a salt or N-oxide thereof, wherein each ofR^(Z5) and R^(Z6) is independently unsubstituted C₁-C₆ alkyl.
 37. Thecompound of claim 36, or a salt or N-oxide thereof, wherein each ofR^(Z5) and R^(Z6) is methyl.
 38. The compound of claim 27, or a salt orN-oxide thereof, wherein R^(Z5) is unsubstituted tetrazolyl ortetrazolyl substituted by C₁-C₆ alkyl; and R^(Z6) is hydrogen.
 39. Thecompound of claim 38, or a salt or N-oxide thereof, wherein R^(Z5) istetrazolyl substituted by C₁-C₆ alkyl.
 40. The compound of claim 27, ora salt or N-oxide thereof, wherein each of R^(Z5) and R^(Z6) isindependently halogen.
 41. The compound of claim 40, or a salt orN-oxide thereof, wherein each of R^(Z5) and R^(Z6) is fluorine.
 42. Thecompound of claim 27, or a salt or N-oxide thereof, wherein R^(Z5) is—O—C₁-C₆ alkylene-P(O)(OH)₂; and R^(Z6) is hydrogen.
 43. The compound ofclaim 27, or a salt or N-oxide thereof, wherein R^(Z5) is —OC(O)R⁸; andR^(Z6) is hydrogen.
 44. The compound of claim 27, or a salt or N-oxidethereof, wherein R^(Z5) and R^(Z6) are taken together with the carbon towhich they are attached to form a carbonyl moiety.
 45. The compound ofclaim 1, or a salt or N-oxide thereof, wherein each of m and n is
 1. 46.The compound of claim 45, or a salt or N-oxide thereof, wherein each ofR^(Z3), R^(Z4), R^(Z5), R^(Z6), R^(Z7) and R^(Z8) is hydrogen.
 47. Thecompound of claim 1, or a salt or N-oxide thereof, wherein X is O. 48.The compound of claim 1, or a salt or N-oxide thereof, wherein X is S.49. The compound of claim 1, or a salt or N-oxide thereof, wherein R^(Z)is hydrogen.
 50. The compound of claim 1, or a salt or N-oxide thereof,wherein R^(Z) is unsubstituted C₁-C₆ alkyl.
 51. The compound of claim50, or a salt or N-oxide thereof, wherein R^(Z) is methyl.
 52. Thecompound of claim 1, or a salt or N-oxide thereof, wherein D ishydrogen.
 53. The compound of claim 1, or a salt or N-oxide thereof,wherein D is unsubstituted C₁-C₆ alkyl or C₁-C₆ alkyl substituted by 1to 5 substituents independently selected from the group consisting ofhydroxy, heteroaryl, and heteroaryl substituted by C₁-C₆ alkyl.
 54. Thecompound of claim 53, or a salt or N-oxide thereof, wherein D is methyl.55. The compound of claim 53, or a salt or N-oxide thereof, wherein D ishydroxyethyl.
 56. The compound of claim 53, or a salt or N-oxidethereof, wherein D is methyl substituted with unsubstituted oxazolyl,oxazolyl substituted by C₁-C₆ alkyl, unsubstituted pyrazolyl, pyrazolylsubstituted by C₁-C₆ alkyl, unsubstituted furanyl, furanyl substitutedby C₁-C₆ alkyl, unsubstituted thiazolyl, or thiazolyl substituted byC₁-C₆ alkyl.
 57. The compound of claim 56, or a salt or N-oxide thereof,wherein D is methyl substituted with oxazol-2-yl, pyrazol-5-yl,1-methylpyrazol-5-yl, furan-2-yl, or thiazol-2-yl.
 58. The compound ofclaim 1, or a salt or N-oxide thereof, wherein D is unsubstitutedphenyl.
 59. The compound of claim 1, or a salt or N-oxide thereof,wherein D is unsubstituted pyridyl or pyridyl substituted by 1 to 5substituents independently selected from the group consisting of alkoxy,amino, halo, hydroxy and thioalkyl.
 60. The compound of claim 59, or asalt or N-oxide thereof, wherein D is unsubstituted pyridyl.
 61. Thecompound of claim 59, or a salt or N-oxide thereof, wherein D is pyridylsubstituted by 1 to 5 substituents independently selected from the groupconsisting of alkoxy, amino, halo, hydroxy and thioalkyl.
 62. Thecompound of claim 59, or a salt or N-oxide thereof, wherein D isselected from the group consisting of 3-pyridyl and 6-fluoro-3-pyridyl.63. The compound of claim 59, or a salt or N-oxide thereof, wherein D isselected from the group consisting of 6-hydroxypyridin-3-yl,6-aminopyridin-3-yl, 6-(methylthio)pyridin-3-yl, and6-ethoxypyridin-3-yl.
 64. The compound of claim 1, or a salt or N-oxidethereof, wherein D is unsubstituted pyrimidyl or pyrimidyl substitutedby 1 to 5 substituents independently selected from the group consistingof alkoxy, amino, halo, hydroxy and thioalkyl.
 65. The compound of claim64, or a salt or N-oxide thereof, wherein D is unsubstituted pyrimidyl.66. The compound of claim 65, or a salt or N-oxide thereof, wherein D ispyrimid-5-yl.
 67. The compound of claim 64, or a salt or N-oxidethereof, wherein D is pyrimidyl substituted by 1 to 5 substituentsindependently selected from the group consisting of alkoxy, amino, halo,hydroxy and thioalkyl.
 68. The compound of claim 1, or a salt or N-oxidethereof, wherein D is unsubstituted pyrazinyl or pyrazinyl substitutedby 1 to 5 substituents independently selected from the group consistingof alkoxy, amino, halo, hydroxy and thioalkyl.
 69. The compound of claim68, or a salt or N-oxide thereof, wherein D is pyrazin-2-yl.
 70. Thecompound of claim 68, or a salt or N-oxide thereof, wherein D ispyrazinyl substituted by 1 to 5 substituents independently selected fromthe group consisting of alkoxy, amino, halo, hydroxy and thioalkyl. 71.The compound of claim 1, or a salt or N-oxide thereof, wherein D isunsubstituted thiazolyl or thiazolyl substituted by 1 to 5 substituentsindependently selected from the group consisting of alkoxy, amino, halo,hydroxy and thioalkyl.
 72. The compound of claim 71, or a salt orN-oxide thereof, wherein D is unsubstituted thiazolyl.
 73. The compoundof claim 71, or a salt or N-oxide thereof, wherein D is substitutedthiazolyl substituted by 1 to 3 substituents independently selected fromthe group consisting of alkoxy, amino, halo, hydroxy and thioalkyl. 74.The compound of claim 73, or a salt or N-oxide thereof, wherein D is5-chlorothiazol-2-yl.
 75. The compound of claim 1, or a salt or N-oxidethereof, wherein D is unsubstituted thiadiazolyl or thiadiazolylsubstituted by 1 to 5 substituents independently selected from the groupconsisting of alkoxy, amino, halo, hydroxy and thioalkyl.
 76. Thecompound of claim 75, or a salt or N-oxide thereof, wherein D isunsubstituted thiadiazolyl.
 77. The compound of claim 1, or a salt orN-oxide thereof, wherein D is unsubstituted C₃-C₈ cycloalkyl.
 78. Thecompound of claim 1, or a salt or N-oxide thereof, wherein D isunsubstituted heterocyclyl or heterocyclyl substituted by 1 to 5substituents independently selected from unsubstituted acyl, acylsubstituted by amino, C₁-C₆ alkyl and oxo.
 79. The compound of claim 78,or a salt or N-oxide thereof, wherein D is unsubstituted pyrrolidin-3-ylor pyrrolidin-3-yl substituted by 1 to 5 substituents independentlyselected from unsubstituted acyl, acyl substituted by amino, C₁-C₆ alkyland oxo.
 80. The compound of claim 79, or a salt or N-oxide thereof,wherein D is 1-acetylpyrrolidin-3-yl.
 81. The compound of claim 78, or asalt or N-oxide thereof, wherein D is unsubstituted piperidin-3-yl orpiperdin-3-yl substituted by 1 to 5 substituents independently selectedfrom unsubstituted acyl, acyl substituted by amino, C₁-C₆ alkyl and oxo.82. The compound of claim 81, or a salt or N-oxide thereof, wherein D is1-(2-amino-2-methylpropanoyl)piperidin-3-yl.
 83. The compound of claim81, or a salt or N-oxide thereof, wherein D is1-isopropylpiperidin-3-yl.
 84. The compound of claim 1, or a salt orN-oxide thereof, wherein E is an unsubstituted 5-membered heteroaryl.85. The compound of claim 1, or a salt or N-oxide thereof, wherein E isunsubstituted pyrazolyl or pyrazolyl substituted by 1 to 3 substituentsindependently selected from the group consisting of unsubstitutedacylamino, hydroxy, unsubstituted C₁-C₆ alkyl, C₁-C₆ alkyl substitutedby hydroxy, unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkylsubstituted by hydroxy or C₁-C₆ alkyl.
 86. The compound of claim 85, ora salt or N-oxide thereof, wherein E is pyrazolyl substituted by 1 to 3substituents independently selected from the group consisting ofunsubstituted acylamino, hydroxy, unsubstituted C₁-C₆ alkyl, C₁-C₆ alkylsubstituted by hydroxy, unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈cycloalkyl substituted by hydroxy or C₁-C₆ alkyl.
 87. The compound ofclaim 86, or a salt or N-oxide thereof, wherein E is selected from thegroup consisting of 5-cyclopropylpyrazol-3-yl,5-cyclopentylpyrazol-3-yl, 5-(isopropyl)pyrazol-3-yl,3-cyclopropylpyrazol-5-yl, 3-cyclopentylpyrazol-5-yl and3-(isopropyl)pyrazol-5-yl.
 88. The compound of claim 86, or a salt orN-oxide thereof, wherein E is selected from the group consisting of5-hydroxypyrazol-3-yl, 5-(2-hydroxypropan-2-yl)pyrazol-3-yl,5-(1-hydroxypropan-2-yl)pyrazol-3-yl,5-(2-hydroxycyclopropyl)pyrazol-3-yl, and 1-hydroxy-5-isopropylpyrazol3-yl.
 89. The compound of claim 1, or a salt or N-oxide thereof, whereinE is unsubstituted imidazolyl or imidazolyl substituted by 1 to 3substituents independently selected from the group consisting ofunsubstituted acylamino, hydroxy, unsubstituted C₁-C₆ alkyl, C₁-C₆ alkylsubstituted by hydroxy, unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈cycloalkyl substituted by hydroxy or C₁-C₆ alkyl.
 90. The compound ofclaim 1, or a salt or N-oxide thereof, wherein E isunsubstituted-isoxazolyl or isoxazolyl substituted by 1 to 3substituents independently selected from the group consisting ofunsubstituted acylamino, hydroxy, unsubstituted C₁-C₆ alkyl, C₁-C₆ alkylsubstituted by hydroxy, unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈cycloalkyl substituted by hydroxy or C₁-C₆ alkyl.
 91. The compound ofclaim 1, or a salt or N-oxide thereof, wherein E is unsubstitutedoxazolyl or oxazolyl substituted by 1 to 3 substituents independentlyselected from the group consisting of unsubstituted acylamino, hydroxy,unsubstituted C₁-C₆ alkyl, C₁-C₆ alkyl substituted by hydroxy,unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkyl substituted byhydroxy or C₁-C₆ alkyl.
 92. The compound of claim 1, or a salt orN-oxide thereof, wherein E is unsubstituted thiazolyl or thiazolylsubstituted by 1 to 3 substituents independently selected from the groupconsisting of unsubstituted acylamino, hydroxy, unsubstituted C₁-C₆alkyl, C₁-C₆ alkyl substituted by hydroxy, unsubstituted C₃-C₈cycloalkyl, and C₃-C₈ cycloalkyl substituted by hydroxy or C₁-C₆ alkyl.93. A compound, or a salt thereof, wherein the compound is selected fromthe group consisting of:1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrrolidin-3-yl)pyrrolidine-2-carboxamide;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(piperidin-3-yl)pyrrolidine-2-carboxamide;N-(1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,1′-cyclopropan]-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,7-dihydrospiro[cyclopenta[d]pyrimidine-6,2′-oxiran]-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonicacid;1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-ylisobutyrate;2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine1-oxide;2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine1-oxide;2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine3-oxide;N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;1-(5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;1-(5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole2-oxide;N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-y77l)pyrrolidine-2-carboxamide;N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;andN-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide.94. A compound, or a salt thereof, wherein the compound is selected fromthe group consisting of:(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)azetidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrazin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;(2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;(2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;(2R,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;(2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide;(2R,3R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;(2S,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;(2R,3S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;(2S,3R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-3-hydroxypyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropylisoxazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxamide;(R)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;(S)-1-(4-(5-cyclopentyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide;(2R,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;(2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;(2R,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;(2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide;(R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methyl-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-piperidin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-piperidin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-piperidin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((R)-piperidin-3-yl)pyrrolidine-2-carboxamide;(R)—N—((R)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N—((S)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N—((S)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N—((R)-1-(2-amino-2-methylpropanoyl)piperidin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4R)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;(2S,4S)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;(2R,4S)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;(2S,4R)—N-(5-chlorothiazol-2-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxypyrrolidine-2-carboxamide;(R)—N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-aminopyridin-3-yl)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;(2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;(2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;(2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxy-N-(pyridin-3-yl)pyrrolidine-2-carboxamide;(2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-methylcyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4,4-dimethylpyrrolidine-2-carboxamide;(2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide;(2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;(2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;(2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;(2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-(5-methyl-2H-tetrazol-2-yl)pyrrolidine-2-carboxamide;(2R,4R)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2S,4S)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4S)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2S,4R)-4-fluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)-4,4-difluoro-N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;(S)-3-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4R)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;(2S,4S)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;(2R,4S)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(1-isopropylpiperidin-3-yl)pyrrolidine-2-carboxamide;(R)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;(S)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)oxazole-5-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-(1-hydroxycyclopropyl)-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2S,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-((1-isopropyl-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;(S)-2-((2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)thiazole-5-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((2-isopropyl-1H-imidazol-5-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-7,7-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(6,6-difluoro-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6-thioxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(2R,4R)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonicacid;(2S,4S)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonicacid;(2R,4S)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonicacid;(2S,4R)-(((1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-yl)oxy)methyl)phosphonicacid;(2R,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-ylisobutyrate;(2S,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-ylisobutyrate;(2R,4S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-ylisobutyrate;(2S,4R)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-5-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-3-ylisobutyrate(R)-2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine1-oxide;(S)-2-fluoro-5-(1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine1-oxide;(R)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine1-oxide;(S)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine1-oxide;(R)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine3-oxide;(S)-2-(2-((6-fluoropyridin-3-yl)carbamoyl)pyrrolidin-1-yl)-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidine3-oxide;(R)—N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-hydroxypyridin-3-yl)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-((R)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-((S)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-((S)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-((R)-5-hydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-((5R,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-((5R,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-((5S,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-((5S,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-((5R,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-((5R,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-((5S,7R)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-((5S,7S)-5,7-dihydroxy-4-((5-isopropyl-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-((5-hydroxy-1H-pyrazol-3-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-4-yl)pyrrolidine-2-carboxamide;(2R,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2S,4S)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(2R,4R)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(2R,4S)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide;(2S,4S)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-yl)pyrrolidine-2-carboxamide(R)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-aminopyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole2-oxide;(S)-3-(2-(2-(6-fluoropyridin-3-ylcarbamoyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-5-isopropyl-1H-pyrazole2-oxide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(1-hydroxy-5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide;(R)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-oxopyrrolidine-2-carboxamide;(R,R)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,S)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,R)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,S)—N-(1-acetylpyrrolidin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(2-hydroxyethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;(S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carbothioamide;(R)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(2-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-(furan-2-ylmethyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S)—N-((1H-pyrazol-5-yl)methyl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-((1-methyl-1H-pyrazol-5-yl)methyl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(oxazol-2-ylmethyl)pyrrolidine-2-carboxamide;(R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;(S)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(thiazol-2-ylmethyl)pyrrolidine-2-carboxamide;(R,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(1-hydroxypropan-2-yl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-(2-hydroxycyclopropyl)-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,R)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(R,S)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(S,R)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(S,S)-1-(6-fluoro-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide;(R,R)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,S)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,R)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,S)—N-(6-fluoropyridin-3-yl)-1-(6-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,R)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R,S)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,R)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(S,S)—N-(6-fluoropyridin-3-yl)-1-(7-hydroxy-4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;(R)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide;and(S)—N-(2-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide.95. The compound of claim 1, wherein the compound is of the formula(I-A):

or a salt or N-oxide thereof.
 96. The compound of claim 95, or a salt orN-oxide thereof, wherein each of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5)and R^(A6) is independently hydrogen, unsubstituted C₁-C₆ alkyl, halo,or taken together with a geminal R^(A(1-6)) group and the carbon towhich they are attached to form a carbonyl moiety or a thiocarbonylmoiety.
 97. The compound of claim 95, or a salt or N-oxide thereof,wherein each of R^(A1), R^(A2), R^(A3), R^(A4), R^(A5) and R^(A6) isindependently hydroxy or hydrogen.
 98. The compound of claim 95, or asalt or N-oxide thereof, wherein each of R^(Z1), R^(Z2), R^(Z3) andR^(Z4) is hydrogen.
 99. The compound of claim 98, or a salt or N-oxidethereof, wherein each of R^(Z5) and R^(Z6) is hydrogen.
 100. Thecompound of claim 98, or a salt or N-oxide thereof, wherein R^(Z5) ishydroxy or —OR¹; and R^(Z6) is hydrogen.
 101. The compound of claim 95,or a salt or N-oxide thereof, wherein R^(Z3) is hydroxy; and R^(Z4) ishydrogen.
 102. The compound of claim 95, or a salt or N-oxide thereof,wherein R^(Z5) is —OR¹; and R^(Z6) is hydrogen.
 103. The compound ofclaim 102, or a salt or N-oxide thereof, wherein R^(Z5) is methoxy. 104.The compound of claim 95, or a salt or N-oxide thereof, wherein R^(Z5)is halogen and R^(Z6) is hydrogen.
 105. The compound of claim 104, or asalt or N-oxide thereof, wherein R^(Z5) is fluorine.
 106. The compoundof claim 95, or a salt or N-oxide thereof, wherein each of R^(Z5) andR^(Z6) is independently unsubstituted C₁-C₆ alkyl.
 107. The compound ofclaim 104, or a salt or N-oxide thereof, wherein each of R^(Z5) andR^(Z6) is methyl.
 108. The compound of claim 95, or a salt or N-oxidethereof, wherein R^(Z5) is unsubstituted tetrazolyl or tetrazolylsubstituted by C₁-C₆ alkyl; and R^(Z6) is hydrogen.
 109. The compound ofclaim 108, or a salt or N-oxide thereof, wherein R^(Z5) is tetrazolylsubstituted by C₁-C₆ alkyl.
 110. The compound of claim 95, or a salt orN-oxide thereof, wherein each of R^(Z5) and R^(Z6) is independentlyhalogen.
 111. The compound of claim 110, or a salt or N-oxide thereof,wherein each of R^(Z5) and R^(Z6) is fluorine.
 112. The compound ofclaim 95, or a salt or N-oxide thereof, wherein R^(Z5) is —O—C₁-C₆alkylene-P(O)(OH)₂; and R^(Z6) is hydrogen.
 113. The compound of claim95, or a salt or N-oxide thereof, wherein R^(Z5) is —OC(O)R⁸; and R^(Z6)is hydrogen.
 114. The compound of claim 95, or a salt or N-oxidethereof, wherein R^(Z5) and R^(Z6) are taken together with the carbon towhich they are attached to form a carbonyl moiety.
 115. The compound ofclaim 95, or a salt or N-oxide thereof, wherein R^(Z) is hydrogen ormethyl.
 116. The compound of claim 95, or a salt or N-oxide thereof,wherein D is unsubstituted pyridyl, pyridyl substituted by 1 to 5substituents independently selected from the group consisting of alkoxy,amino, halo, hydroxy and thioalkyl; unsubstituted pyrimidyl, pyrimidylsubstituted by 1 to 5 substituents independently selected from the groupconsisting of alkoxy, amino, halo, hydroxy and thioalkyl; unsubstitutedpyrazinyl, or pyrazinyl substituted by 1 to 5 substituents independentlyselected from the group consisting of alkoxy, amino, halo, hydroxy andthioalkyl.
 117. The compound of claim 116, or a salt or N-oxide thereof,wherein D is selected from the group consisting of 6-fluoro-3-pyridyl,3-pyridyl, pyrimid-5-yl and pyrazin-2-yl.
 118. The compound of claim 95,or a salt or N-oxide thereof, wherein D is unsubstituted C₁-C₆ alkyl orC₁-C₆ alkyl substituted by 1 to 5 substituents independently selectedfrom the group consisting of hydroxy, heteroaryl, and heteroarylsubstituted by C₁-C₆ alkyl.
 119. The compound of claim 118, or a salt orN-oxide thereof, wherein D is methyl.
 120. The compound of claim 118, ora salt or N-oxide thereof, wherein D is methyl substituted withunsubstituted oxazolyl, oxazolyl substituted by C₁-C₆ alkyl,unsubstituted pyrazolyl, pyrazolyl substituted by C₁-C₆ alkyl,unsubstituted furanyl, furanyl substituted by C₁-C₆ alkyl, unsubstitutedthiazolyl, or thiazolyl substituted by C₁-C₆ alkyl.
 121. The compound ofclaim 120, or a salt or N-oxide thereof, wherein D is methyl substitutedwith oxazol-2-yl, pyrazol-5-yl, 1-methylpyrazol-5-yl, furan-2-yl, orthiazol-2-yl.
 122. The compound of claim 95, or a salt or N-oxidethereof, wherein D is unsubstituted piperdin-3-yl or piperdin-3-ylsubstituted by 1 to 5 substituents independently selected fromunsubstituted acyl, acyl substituted by amino.
 123. The compound ofclaim 122, or a salt or N-oxide thereof, wherein D is1-(2-amino-2-methylpropanoyl)piperidin-3-yl.
 124. The compound of claim122, or a salt or N-oxide thereof, wherein D is1-isopropylpiperidin-3-yl.
 125. The compound of claim 95, or a salt orN-oxide thereof, wherein D is unsubstituted thiazolyl or thiazolylsubstituted by 1 to 3 substituents independently selected from the groupconsisting of alkoxy, amino, halo, hydroxy and thioalkyl.
 126. Thecompound of claim 95, or a salt or N-oxide thereof, wherein D isunsubstituted thiadiazolyl or thiadiazolyl substituted by 1 to 3substituents independently selected from the group consisting of alkoxy,amino, halo, hydroxy and thioalkyl.
 127. The compound of claim 95, or asalt or N-oxide thereof, wherein D is unsubstituted pyrrolidin-3-yl orpyrrolidin-3-yl substituted by 1 to 5 substituents independentlyselected from unsubstituted acyl, acyl substituted by amino.
 128. Thecompound of claim 95, or a salt or N-oxide thereof, wherein E isunsubstituted pyrazolyl, pyrazolyl substituted by 1 to 3 substituentsindependently selected from the group consisting of unsubstitutedacylamino, hydroxy, unsubstituted C₁-C₆ alkyl, C₁-C₆ alkyl substitutedby hydroxy, unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkylsubstituted by hydroxy or C₁-C₆ alkyl; unsubstituted isoxazolyl,isoxazolyl substituted by 1 to 3 substituents independently selectedfrom the group consisting of unsubstituted acylamino, hydroxy,unsubstituted C₁-C₆ alkyl, C₁-C₆ alkyl substituted by hydroxy,unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkyl substituted byhydroxy or C₁-C₆ alkyl; unsubstituted imidazolyl, imidazolyl substitutedby 1 to 3 substituents independently selected from the group consistingof unsubstituted acylamino, hydroxy, unsubstituted C₁-C₆ alkyl, C₁-C₆alkyl substituted by hydroxy, unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈cycloalkyl substituted by hydroxy or C₁-C₆ alkyl; unsubstitutedoxazolyl, oxazolyl substituted by 1 to 3 substituents independentlyselected from the group consisting of unsubstituted acylamino, hydroxy,unsubstituted C₁-C₆ alkyl, C₁-C₆ alkyl substituted by hydroxy,unsubstituted C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkyl substituted byhydroxy or C₁-C₆ alkyl; unsubstituted thiazole thiazolyl, or thiazolylsubstituted by 1 to 3 substituents independently selected from the groupconsisting of unsubstituted acylamino, hydroxy, unsubstituted C₁-C₆alkyl, C₁-C₆ alkyl substituted by hydroxy, unsubstituted C₃-C₈cycloalkyl, and C₃-C₈ cycloalkyl substituted by hydroxy or C₁-C₆ alkyl.129. The compound of claim 128, or a salt or N-oxide thereof, wherein Eis selected from the group consisting of 5-cyclopropylpyrazol-3-yl,5-cyclopentylpyrazol-3-yl, 5-(isopropyl)pyrazol-3-yl,3-cyclopropylpyrazol-5-yl, 3-cyclopentylpyrazol-5-yl,3-(isopropyl)pyrazol-5-yl, and 3-(isopropyl)isoxazol-5-yl.
 130. Thecompound of claim 128, or a salt or N-oxide thereof, wherein E isselected from the group consisting of 5-hydroxypyrazol-3-yl,5-(2-hydroxypropan-2-yl)pyrazol-3-yl,5-(1-hydroxypropan-2-yl)pyrazol-3-yl,5-(2-hydroxycyclopropyl)pyrazol-3-yl, and1-hydroxy-5-isopropylpyrazol-3-yl.
 131. A pharmaceutical compositioncomprising a compound of claim 1, or a salt or N-oxide thereof, and apharmaceutically acceptable carrier.
 132. A kit comprising a compound ofclaim 1, or an N-oxide thereof, or a pharmaceutically acceptable saltthereof.
 133. A pharmaceutical composition comprising a compound ofclaim 93, or a salt thereof, and a pharmaceutically acceptable carrier.134. A kit comprising a compound of claim 93, or a pharmaceuticallyacceptable salt thereof.
 135. A pharmaceutical composition comprising acompound of claim 94, or a salt thereof, and a pharmaceuticallyacceptable carrier.
 136. A kit comprising a compound of claim 94, or apharmaceutically acceptable salt thereof.
 137. A pharmaceuticalcomposition comprising a compound of claim 95, or a salt or N-oxidethereof, and a pharmaceutically acceptable carrier.
 138. A kitcomprising a compound of claim 95, or an N-oxide thereof, or apharmaceutically acceptable salt thereof.